nodgoРоссийский журнал детской гематологии и онкологии (РЖДГиО)Russian Journal of Pediatric Hematology and Oncology2311-12672413-5496LTD “Graphica”10.21682/2311-1267-2021-8-2-73-83nodgo-723Research ArticleОБЗОРЫ ЛИТЕРАТУРЫLITERATURE REVIEWSПрогностические биомаркеры эффективности иммунотерапии злокачественных новообразований ингибиторами контрольных точек иммунного ответаPredictive biomarkers of inhibitors immune checkpoints therapy in malignant tumorshttps://orcid.org/0000-0002-0132-167XКиселевскийМ. В.KiselevskyM. V.

Киселевский Михаил Валентинович - доктор медицинских наук, профессор, заведующий лабораторией клеточного иммунитета НИИ экспериментальной диагностики и терапии опухолей НМИЦ онкологии им. Н.Н. Блохина.

115478, Москва, Каширское шоссе, 23.

SPIN-код: 8687-2387

Dr. of Sci. (Med.), Professor, Head of the Laboratory of Cellular Immunity Research Institute for Experimental Diagnostics and Therapy of Tumors at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia.

23 Kashirskoe Shosse, Moscow, 115478.

SPIN-code: 8687-2387

kisele@inbox.ruhttps://orcid.org/0000-0001-7150-5071СамойленкоИ. В.SamoylenkoI. V.

Кандидат медицинских наук старший научный сотрудник отделения онкодерматологии НИИ клинической онкологии НМИЦ онкологии им. Н.Н. Блохина.

115478, Москва, Каширское шоссе, 23.

SPIN-код: 3691-8923

Cand. of Sci. (Med.), Senior Researcher Surgical Department of Oncodermatology Research Institute of Clinical Oncology at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia.

23 Kashirskoe Shosse, Moscow, 115478.

SPIN-code: 3691-8923

i.samoylenko@ronc.ruhttps://orcid.org/0000-0001-8021-2051ЖарковаО. В.ZharkovaO. V.

Кандидат медицинских наук, заместитель главного врача Камчатского краевого онкологического диспансера.

683024, Петропавловск-Камчатский, ул. Лукашевского, 15.

Cand. of Sci. (Med.), Deputy Chief Physician of the Kamchatka Regional Oncological Dispensary.

15 Lukashevsky St., Petropavlovsk-Kamchatsky, 683024.

olga-zh1212@ya.ruhttps://orcid.org/0000-0002-1672-4738ЗиганшинаН. В.ZiganshinaN. V.

Главный врач Камчатского краевого онкологического диспансера.

683024, Петропавловск-Камчатский, ул. Лукашевского, 15.

Chief Physician of the Kamchatka Regional Oncological Dispensary.

15 Lukashevsky St., Petropavlovsk-Kamchatsky, 683024.

victorya02.06@bk.ruhttps://orcid.org/0000-0001-7722-9821ПеткевичА. А.PetkevichA. A.

Лаборант-исследователь лаборатории клеточного иммунитета НИИ экспериментальной диагностики и терапии опухолей НМИЦ онкологии им. Н.Н. Блохина.

115478, Москва, Каширское шоссе, 23.

SPIN-код: 8620-6202

Research Assistant Laboratory of Cellular Immunity Research Institute Experimental Diagnosis and Therapy of Tumors at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia.

23 Kashirskoe Shosse, Moscow, 115478.

SPIN-code: 8620-6202

gluksworld@gmail.comhttps://orcid.org/0000-0002-2840-1186СитдиковаС. М.SitdikovaS. M.

Кандидат биологических наук, старший научный сотрудник лаборатории клеточного иммунитета НИИ экспериментальной диагностики и терапии опухолей НМИЦ онкологии им. Н.Н. Блохина.

115478, Москва, Каширское шоссе, 23.

SPIN-код: 4124-5769

Cand. of Sci. (Biol.), Senior Researcher Laboratory of Cellular Immunity Research Institute Experimental Diagnosis and Therapy of Tumors at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia.

23 Kashirskoe Shosse, Moscow, 115478.

SPIN-code: 4124-5769

suriyasitdikova@yandex.ruhttps://orcid.org/0000-0002-5489-1879СулеймановаА. М.SuleymanovaA. M.

Врач-детский онколог НИИ детской онкологии и гематологии НМИЦ онкологии им. Н.Н. Блохина.

115478, Москва, Каширское шоссе, 23.

Pediatric Oncologist Research Institute of Pediatric Oncology and Hematology at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia.

23 Kashirskoe Shosse, Moscow, 115478.

aminasuleymanova313@gmail.comhttps://orcid.org/0000-0002-7846-3473СагоянГ. Б.SagoyanG. B.

Врач-детский онколог НИИ детской онкологии и гематологии НМИЦ онкологии им. Н.Н. Блохина.

115478, Москва, Каширское шоссе, 23.

SPIN-код: 6304-0159

Pediatric Oncologist Research Institute of Pediatric Oncology and Hematology at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia.

23 Kashirskoe Shosse, Moscow, 115478.

SPIN-code: 6304-0159

sagoyan-garik@mail.ruhttps://orcid.org/0000-0002-1925-2457ЕфимоваМ. М.EfimovaM. M.

Врач-детский онколог НИИ детской онкологии и гематологии НМИЦ онкологии им. Н.Н. Блохина.

115478, Москва, Каширское шоссе, 23.

Pediatric Oncologist Research Institute of Pediatric Oncology and Hematology at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia.

23 Kashirskoe Shosse, Moscow, 115478.

kivi123987@gmail.comhttps://orcid.org/0000-0002-2945-284XКиргизовК. И.KirgizovK. I.

Кандидат медицинских наук, заместитель директора по научной и образовательной работе НИИ детской онкологии и гематологии НМИЦ онкологии им. Н.Н. Блохина.

115478, Москва, Каширское шоссе, 23.

SPIN-код: 3803-6370

Cand. of Sci. (Med.), Deputy Director for Scientific and Educational Work of Research Institute of Pediatric Oncology and Hematology atN.N.Blokhin National Medical Research CenterofOncology, Ministry of Health of Russia.

23 Kashirskoe Shosse, Moscow, 115478.

SPIN-code: 3803-6370

k.kirgizov@ronc.ruhttps://orcid.org/0000-0001-6131-1783ВарфоломееваС. Р.VarfolomeevaS. R.

Доктор медицинских наук, профессор, директор НИИ детской онкологии и гематологии аппарата управления НМИЦ онкологии им. Н.Н. Блохина.

115478, Москва, Каширское шоссе, 23.

Dr. of Sci. (Med.), Professor, Director of the Research Institute of Pediatric Oncology and Hematology at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia.

23 Kashirskoe Shosse, Moscow, 115478.

s.varfolomeeva@ronc.ruНМИЦ онкологии им. Н.Н. Блохина Минздрава РоссииРоссияN.N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of RussiaRussian FederationКамчатский краевой онкологический диспансерРоссияKamchatka Regional Oncological DispensaryRussian Federation202112072021827383Copyright © Киселевский М.В., Самойленко И.В., Жаркова О.В., Зиганшина Н.В., Петкевич А.А., Ситдикова С.М., Сулейманова А.М., Сагоян Г.Б., Ефимова М.М., Киргизов К.И., Варфоломеева С.Р., 20212021Киселевский М.В., Самойленко И.В., Жаркова О.В., Зиганшина Н.В., Петкевич А.А., Ситдикова С.М., Сулейманова А.М., Сагоян Г.Б., Ефимова М.М., Киргизов К.И., Варфоломеева С.Р.Kiselevsky M.V., Samoylenko I.V., Zharkova O.V., Ziganshina N.V., Petkevich A.A., Sitdikova S.M., Suleymanova A.M., Sagoyan G.B., Efimova M.M., Kirgizov K.I., Varfolomeeva S.R.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nodgo.org/jour/article/view/723

Терапия препаратами ингибиторов иммунных контрольных точек (ИКТ) является успешной стратегией иммунотерапии (ИТ), обладающей высокой эффективностью у ряда пациентов при меланоме, немелкоклеточном раке легкого, раке мочевого пузыря, раке молочной железы и других формах злокачественных новообразований. Однако существует группа пациентов, доля которой варьируется в зависимости от нозологии, не отвечающих на подобную терапию, что делает актуальным вопрос поиска предиктивных маркеров терапии ИКТ для персонификации ИТ. В отдельную группу можно выделить пациентов детского возраста, для которых показания к терапии и ее эффективность в настоящее время изучаются. В обзоре обобщены теоретические аспекты и результаты клинических испытаний различных вариантов предикторов эффективности ИТ с использованием современных баз данных. В результате проведенного анализа установлено, что основными кандидатами на роль подобных маркеров являются опухоль-инфильтрирующие лимфоциты (ОИЛ) и лимфоциты периферической крови (ЛПК), а также их субпопуляционный состав. Важное значение для прогноза эффективности данного вида ИТ может иметь также экспрессия маркеров PD1 (рецептор запрограммированной гибели 1) и PDL1 (лиганд рецептора запрограммированной гибели 1) в опухолевой ткани. Наиболее перспективной с точки зрения клинической значимости является комбинация исследования субпопуляционного состава ОИЛ и ЛПК в сочетании с определением уровня экспрессии рецепторов PD1 и PDL1 в образцах опухоли.

Проведен поиск доступных источников литературы, опубликованных в базах данных PubMed, Scopus, Web of Science, eLibrary, РИНЦ. В обзор включены 82 источника.

Immune checkpoint inhibitors (ICT) therapy is a successful immunotherapy (IT) strategy that is quite effective in a number of patients with non-small cell lung cancer, melanoma, bladder cancer, breast cancer and others. Nevertheless, there is a need in predictive markers for ICT therapy for personalized IT as far as there is a large group of patients, the proportion of which varies depending on the tumor, who do not have a clinical response to such therapy. The review summarizes the theoretical aspects and results of clinical trials dedicated to various clinical efficiency predictor using modern databases. As a result of the analysis it is established that the main candidates for the role of such markers are tumor infiltrating lymphocytes and their subpopulations, peripheral blood lymphocytes (PBL) and their subpopulations. PD1 (programmed death receptor 1) and PDL1 (programmed death receptor ligand 1) expression in tumor tissue can also be important for predicting IT efficiency. The most promising predictive biomarker meaning the most clinically relevant is a combination of the PBL subpopulations study and PD1 and PDL1 expression on the tumor cells.

PubMed, Scopus, Web of Science, eLibrary, Russian Science Citation Index databases were searched for the available appropriate literature reports. The authors included 82 in the given review.

терапия ингибиторами иммунных контрольных точекбиомаркерыпредикцияimmune checkpoint inhibitors therapybiomarkerspredictionИсследование проведено за счет средств федерального бюджета в рамках государственного задания на выполнение экспериментальной научной разработки «Разработка метода иммунного профилирования опухоли для определения прогноза течения заболевания и ответа на лекарственную терапию у пациентов с отдельными формами злокачественных новообразований» № госрегистрации AAAA-A18-118022890094-4.The study was carried out at the expense of the federal budget within the framework of the state task for the implementation of an experimental scientific development “Development of a method of immune profiling of a tumor to determine the prognosis of the course of the disease and response to drug therapy in patients with certain forms of malignant neoplasms” state registration No. AAAA-A18-118022890094-4.ReferencesLarkin J., Chiarion-Sileni V., Gonzales R., Grob J.J., Cowey C.L., Lao C.D., Schadendorf D., Dummer R., Smylie M., Rutkowski P., Ferrucci P.F., Hill A., Wagstaff J., Carlino M.S., Haanen J.B., Maio M., Marquez-Rodas I., McArthur G.A., Ascierto P.A., Long G.V., Callahan M.K., Postow M.A., Grossmann K., Sznol M., Dreno B., Bastholt L., Yang A., Rollin L.M., Horak C., Hodi F.S., Wolchok J.D. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23-34. doi: 10.1056/NEJMoa1504030.Larkin J., Chiarion-Sileni V., Gonzales R., Grob J.J., Cowey C.L., Lao C.D., Schadendorf D., Dummer R., Smylie M., Rutkowski P., Ferrucci P.F., Hill A., Wagstaff J., Carlino M.S., Haanen J.B., Maio M., Marquez-Rodas I., McArthur G.A., Ascierto P.A., Long G.V., Callahan M.K., Postow M.A., Grossmann K., Sznol M., Dreno B., Bastholt L., Yang A., Rollin L.M., Horak C., Hodi F.S., Wolchok J.D. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23-34. doi: 10.1056/NEJMoa1504030.Capalbo C., Scafetta G., Filetti M., Marchetti P., Bartolazzi A. Predictive Biomarkers for Checkpoint Inhibitor-Based Immunotherapy: The Galectin-3 Signature in NSCLCs. Int J Mol Sci 2019;20(7):E1607. doi: 10.3390/ijms20071607.Capalbo C., Scafetta G., Filetti M., Marchetti P., Bartolazzi A. Predictive Biomarkers for Checkpoint Inhibitor-Based Immunotherapy: The Galectin-3 Signature in NSCLCs. Int J Mol Sci 2019;20(7):E1607. doi: 10.3390/ijms20071607.Dunn G.P., Bruce A.T., Ikeda H., Old L.J., Schreiber R.D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002;3(11):991-8. doi: 10.1038/ni1102-991.Dunn G.P., Bruce A.T., Ikeda H., Old L.J., Schreiber R.D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002;3(11):991-8. doi: 10.1038/ni1102-991.Schreiber R.D., Old L.J., Smyth M.J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011;331(6024):1565-70. doi: 10.1126/science.1203486.Schreiber R.D., Old L.J., Smyth M.J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011;331(6024):1565-70. doi: 10.1126/science.1203486.Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Canc 2012;12(4):252-64. doi: 10.1126/science.1203486.Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Canc 2012;12(4):252-64. doi: 10.1126/science.1203486.Leach D.R., Krummel M.F., Allison J.P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271(5256):1734-6. doi: 10.1126/science.271.5256.1734.Leach D.R., Krummel M.F., Allison J.P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271(5256):1734-6. doi: 10.1126/science.271.5256.1734.Curran M.A., Montalvo W., Yagita H., Allison J.P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci USA 2010;107(9):4275-80. doi: 10.1073/pnas.0915174107.Curran M.A., Montalvo W., Yagita H., Allison J.P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci USA 2010;107(9):4275-80. doi: 10.1073/pnas.0915174107.Shi L.Z., Fu T., Guan B. Interdependent IL-7 and IFN-gamma signalling in T-cell controls tumour eradication by combined alpha-CTLA-4+alpha-PD-1 therapy. Nat Commun 2016;7:12335. doi: 10.1038/ncomms12335.Shi L.Z., Fu T., Guan B. Interdependent IL-7 and IFN-gamma signalling in T-cell controls tumour eradication by combined alpha-CTLA-4+alpha-PD-1 therapy. Nat Commun 2016;7:12335. doi: 10.1038/ncomms12335.Hodi F.S., O'Day S.J., McDermott D. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711-23. doi: 10.1056/NEJMoa1003466Hodi F.S., O'Day S.J., McDermott D. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711-23. doi: 10.1056/NEJMoa1003466Ma W., Gilligan B.M, Yuan J., Li T. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol 2016;9:47. doi: 10.1186/s13045-016-0277-y.Ma W., Gilligan B.M, Yuan J., Li T. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol 2016;9:47. doi: 10.1186/s13045-016-0277-y.Sharma P., Hu-Lieskovan S., Wargo J.A., Ribas A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell 2017;168:707-23. doi: 10.1016/j.cell.2017.01.017.Sharma P., Hu-Lieskovan S., Wargo J.A., Ribas A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell 2017;168:707-23. doi: 10.1016/j.cell.2017.01.017.Thorsson V., Gibbs D.L., Brown S.D. The Immune Landscape of Cancer. Immunity 2018;48:812-30. doi: 10.1016/j.immuni.2018.03.023.Thorsson V., Gibbs D.L., Brown S.D. The Immune Landscape of Cancer. Immunity 2018;48:812-30. doi: 10.1016/j.immuni.2018.03.023.Weber S., D'Angelo S.P., Minor D., Hodi F.S., Gutzmer R., Neyns B., Hoeller C., Khushalani N.I., Miller W.H. Jr, Lao C.D., Linette G.P., Thomas L., Lorigan P., Grossmann K.F., Hassel J.C., Maio M., Sznol M., Ascierto P.A., Mohr P., Chmielowski B., Bryce A., Svane I.M., Grob J.-J., Krackhardt A.M., Horak C., Lambert A., Yang A.S., Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16:375. doi: 10.1016/S1470-2045(15)70076-8.Weber S., D'Angelo S.P., Minor D., Hodi F.S., Gutzmer R., Neyns B., Hoeller C., Khushalani N.I., Miller W.H. Jr, Lao C.D., Linette G.P., Thomas L., Lorigan P., Grossmann K.F., Hassel J.C., Maio M., Sznol M., Ascierto P.A., Mohr P., Chmielowski B., Bryce A., Svane I.M., Grob J.-J., Krackhardt A.M., Horak C., Lambert A., Yang A.S., Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16:375. doi: 10.1016/S1470-2045(15)70076-8.Wolchok J.D., Kluger H., Callahan M.K. Postow M.A., Rizvi N.A., Lesokhin A.M., Segal N.H., Ariyan C.E., Gordon R.A., Reed K., Burke M.M., Caldwell A., Kronenberg S.A., Agunwamba B.U., Zhang X., Lowy I., Inzunza H.D., Feely W., Horak C.E., Hong Q., Korman A.J., Wigginton J.M., Gupta A., Sznol M. Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl Med 2013;369:122-33. doi: 10.1056/NEJMoa1302369.Wolchok J.D., Kluger H., Callahan M.K. Postow M.A., Rizvi N.A., Lesokhin A.M., Segal N.H., Ariyan C.E., Gordon R.A., Reed K., Burke M.M., Caldwell A., Kronenberg S.A., Agunwamba B.U., Zhang X., Lowy I., Inzunza H.D., Feely W., Horak C.E., Hong Q., Korman A.J., Wigginton J.M., Gupta A., Sznol M. Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl Med 2013;369:122-33. doi: 10.1056/NEJMoa1302369.Pons-Tostivint E., Latouche A., Vaflard P., Ricci F., Loirat D., Hescot S., Sablin M.-P., Rouzier R., Kamal M., Morel C., Lecerf C., Servois V., Paoletti X., Le Tourneau C. Comparative analysis of durable responses on immune checkpoint inhibitors versus other systemic therapies: a pooled analysis of phase III trials. JCO Precis Oncol 2019;3:1-10. doi: 10.1200/po.18.0011415.Pons-Tostivint E., Latouche A., Vaflard P., Ricci F., Loirat D., Hescot S., Sablin M.-P., Rouzier R., Kamal M., Morel C., Lecerf C., Servois V., Paoletti X., Le Tourneau C. Comparative analysis of durable responses on immune checkpoint inhibitors versus other systemic therapies: a pooled analysis of phase III trials. JCO Precis Oncol 2019;3:1-10. doi: 10.1200/po.18.0011415.Maibach F., Sadozai H., Seyed Jafari S.M., Hunger R.E., Schenk M. Tumor-Infiltrating Lymphocytes and Their Prognostic Value in Cutaneous Melanoma. Front Immunol 2020;11:2105. doi: 10.3389/fimmu.2020.0210.Maibach F., Sadozai H., Seyed Jafari S.M., Hunger R.E., Schenk M. Tumor-Infiltrating Lymphocytes and Their Prognostic Value in Cutaneous Melanoma. Front Immunol 2020;11:2105. doi: 10.3389/fimmu.2020.0210.Nelson M.A., Ngamcherdtrakul W., Luoh S.W., Yantasee W. Prognostic and therapeutic role of tumor-infiltrating lymphocyte subtypes in breast cancer. Cancer Metastasis Rev 2021. doi: 10.1007/s10555-021-09968-0.Nelson M.A., Ngamcherdtrakul W., Luoh S.W., Yantasee W. Prognostic and therapeutic role of tumor-infiltrating lymphocyte subtypes in breast cancer. Cancer Metastasis Rev 2021. doi: 10.1007/s10555-021-09968-0.Geng Y., Shao Y., He W., Hu W., Xu Y., Chen J., Wu C., Jiang J. Prognostic Role of Tumor-Infiltrating Lymphocytes in Lung Cancer: a Meta-Analysis. Cell Physiol Biochem 2015;37(4):1560-71. doi: 10.1159/00043852.Geng Y., Shao Y., He W., Hu W., Xu Y., Chen J., Wu C., Jiang J. Prognostic Role of Tumor-Infiltrating Lymphocytes in Lung Cancer: a Meta-Analysis. Cell Physiol Biochem 2015;37(4):1560-71. doi: 10.1159/00043852.Nosho K., Baba Y., Tanaka N., Shima K., Hayashi M., Meyerhardt J.A., Giovannucci E., Dranoff G., Fuchs C.S, Ogino S. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 2010;222(4):350-66. doi: 10.1002/path.2774.Nosho K., Baba Y., Tanaka N., Shima K., Hayashi M., Meyerhardt J.A., Giovannucci E., Dranoff G., Fuchs C.S, Ogino S. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 2010;222(4):350-66. doi: 10.1002/path.2774.Schirosi L., Saponaro C., Giotta F., Popescu O., Pastena M.I., Scarpi E., Mangia A. Tumor Infiltrating Lymphocytes and NHERF1 Impact on Prognosis of Breast Cancer Patients. Transl Oncol 2020;13(2):186-92. doi: 10.1016/j.tranon.2019.10.020.Schirosi L., Saponaro C., Giotta F., Popescu O., Pastena M.I., Scarpi E., Mangia A. Tumor Infiltrating Lymphocytes and NHERF1 Impact on Prognosis of Breast Cancer Patients. Transl Oncol 2020;13(2):186-92. doi: 10.1016/j.tranon.2019.10.020.Dieci M.V., Radosevic-Robin N., Fineberg S., van den Eynden G., Ternes N., Penault-Llorca F., Pruneri G., D'Alfonso T.M., Demaria S., Castaneda C., Sanchez J., Badve S., Michiels S., Bossuyt V., Rojo F., Singh B., Nielsen T., Viale G., Kim S.R., Hewitt S., Wienert S., Loibl S., Rimm D., Symmans F., Denkert C., Adams S., Loi S., Salgado R. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International ImmunoOncology Biomarker Working Group on Breast Cancer. Semin Cancer Biol 2018;52(Pt 2):16-25. doi: 10.1016/j.semcancer.2017.10.003.Dieci M.V., Radosevic-Robin N., Fineberg S., van den Eynden G., Ternes N., Penault-Llorca F., Pruneri G., D'Alfonso T.M., Demaria S., Castaneda C., Sanchez J., Badve S., Michiels S., Bossuyt V., Rojo F., Singh B., Nielsen T., Viale G., Kim S.R., Hewitt S., Wienert S., Loibl S., Rimm D., Symmans F., Denkert C., Adams S., Loi S., Salgado R. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International ImmunoOncology Biomarker Working Group on Breast Cancer. Semin Cancer Biol 2018;52(Pt 2):16-25. doi: 10.1016/j.semcancer.2017.10.003.Liu S., Foulkes W.D., Leung S., Lau S., Kos Z., Nielsen T.O. Prognostic significance of FOXP3+ tumor infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration. Breast Cancer Res 2014;16(5):432. doi: 10.1186/s13058-014-0432-8.Liu S., Foulkes W.D., Leung S., Lau S., Kos Z., Nielsen T.O. Prognostic significance of FOXP3+ tumor infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration. Breast Cancer Res 2014;16(5):432. doi: 10.1186/s13058-014-0432-8.Barnes T.A., Amir E. HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer. Br J Cancer 2017;117:451-60. doi: 10.1038/bjc.2017.220.Barnes T.A., Amir E. HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer. Br J Cancer 2017;117:451-60. doi: 10.1038/bjc.2017.220.Teschendorff A.E., Gomez S., Arenas A., El-Ashry D., Schmidt M., Gehrmann M., Caldas C. Improved prognostic classification of breast cancer defined by antagonistic activation patterns of immune response pathway modules BMC. Cancer 2010;10:604. doi: 10.1186/1471-2407-10-604.Teschendorff A.E., Gomez S., Arenas A., El-Ashry D., Schmidt M., Gehrmann M., Caldas C. Improved prognostic classification of breast cancer defined by antagonistic activation patterns of immune response pathway modules BMC. Cancer 2010;10:604. doi: 10.1186/1471-2407-10-604.Denkert C., Loibl S., Noske A., Roller M., Muller B.M., Komor M., Budczies J., Darb-Esfahani S., Kronenwett R., Hanusch C., von Torne C., Weichert W., Engels K., Solbach C., Schrader I., Dietel M., von Minckwitz G. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 2010;28:105-13. doi: 10.1200/JCO.2009.23.7370.Denkert C., Loibl S., Noske A., Roller M., Muller B.M., Komor M., Budczies J., Darb-Esfahani S., Kronenwett R., Hanusch C., von Torne C., Weichert W., Engels K., Solbach C., Schrader I., Dietel M., von Minckwitz G. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 2010;28:105-13. doi: 10.1200/JCO.2009.23.7370.Qi W., Huang X., Wang J. Correlation between Th17 cells and tumor microenvironment. Cell Immunol 2013;285:18-22. doi: 10.1016/j.cellimm.2013.06.001.Qi W., Huang X., Wang J. Correlation between Th17 cells and tumor microenvironment. Cell Immunol 2013;285:18-22. doi: 10.1016/j.cellimm.2013.06.001.Mahmoud S.M., Lee A.H., Paish E.C., Macmillan R.D., Ellis I.O., Green A.R. The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat 2012;132:545-53. doi: 10.1007/s10549-011-1620-1.Mahmoud S.M., Lee A.H., Paish E.C., Macmillan R.D., Ellis I.O., Green A.R. The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat 2012;132:545-53. doi: 10.1007/s10549-011-1620-1.Mansfield A.S., Murphy S.J., Peikert T., Yi E.S., Vasmatzis G., Wigle D.A., Aubry M.C. Heterogeneity of programmed cell death ligand 1 expression in multifocal lung cancer. Clin Cancer Res 2016;22:2177-82. doi: 10.1158/1078-0432.CCR-15-2246.Mansfield A.S., Murphy S.J., Peikert T., Yi E.S., Vasmatzis G., Wigle D.A., Aubry M.C. Heterogeneity of programmed cell death ligand 1 expression in multifocal lung cancer. Clin Cancer Res 2016;22:2177-82. doi: 10.1158/1078-0432.CCR-15-2246.Pages F., Berger A., Camus M., Sanchez-Cabo F., Costes A., Molidor R., Mlecnik B., Kirilovsky A., Nilsson M., Damotte D., Meatchi T., Bruneval P., Cugnenc P.H., Trajanoski Z., Fridman W.H., Galon J. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005;353:2654-66. doi: 10.1056/NEJMoa051424.Pages F., Berger A., Camus M., Sanchez-Cabo F., Costes A., Molidor R., Mlecnik B., Kirilovsky A., Nilsson M., Damotte D., Meatchi T., Bruneval P., Cugnenc P.H., Trajanoski Z., Fridman W.H., Galon J. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005;353:2654-66. doi: 10.1056/NEJMoa051424.Davis A.A., Patel V.G. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J Immunother Cancer 2019;7:278 doi: 10.1186/s40425-019-0768-9.Davis A.A., Patel V.G. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J Immunother Cancer 2019;7:278 doi: 10.1186/s40425-019-0768-9.Reck M., Rodriguez-Abreu D., Robinson A.G., Hui R., Csoszi T., Fulop A. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Cancer. N Engl J Med 2016;375(19):1823-33. doi: 10.1056/NEJMoa1606774.Reck M., Rodriguez-Abreu D., Robinson A.G., Hui R., Csoszi T., Fulop A. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Cancer. N Engl J Med 2016;375(19):1823-33. doi: 10.1056/NEJMoa1606774.Herbst R.S., Baas P., Kim D.W., Felip E., Perez-Gracia J.L., Han J.Y., Molina J., Kim J.H., Arvis C.D., Ahn M.J., Majem M., Fidler M.J., de Castro G. Jr, Garrido M., Lubiniecki G.M., Shentu Y., Im E., Dolled-Filhart M., Garon E.B. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387(10027):1540-50. doi: 10.1016/S0140-6736(15)01281-7.Herbst R.S., Baas P., Kim D.W., Felip E., Perez-Gracia J.L., Han J.Y., Molina J., Kim J.H., Arvis C.D., Ahn M.J., Majem M., Fidler M.J., de Castro G. Jr, Garrido M., Lubiniecki G.M., Shentu Y., Im E., Dolled-Filhart M., Garon E.B. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387(10027):1540-50. doi: 10.1016/S0140-6736(15)01281-7.Rizk E.M., Gartrell R.D., Barker L.W., Esancy C.L., Finkel G.G., Bordbar D.D., Saenger Y.M. Prognostic and Predictive Immunohistochemistry-Based Biomarkers in Cancer and Immunotherapy. Hematol Oncol Clin North Am 2019;33(2):291-9. doi: 10.1016/j.hoc.2018.12.005.Rizk E.M., Gartrell R.D., Barker L.W., Esancy C.L., Finkel G.G., Bordbar D.D., Saenger Y.M. Prognostic and Predictive Immunohistochemistry-Based Biomarkers in Cancer and Immunotherapy. Hematol Oncol Clin North Am 2019;33(2):291-9. doi: 10.1016/j.hoc.2018.12.005.Lança T., Silva-Santos B. The split nature of tumor-infi ltrating leukocytes: Implications for cancer surveillance and immunotherapy. Oncoimmunol 2012;1(5):717–25. doi: 10.4161/onci.20068.Lança T., Silva-Santos B. The split nature of tumor-infi ltrating leukocytes: Implications for cancer surveillance and immunotherapy. Oncoimmunol 2012;1(5):717–25. doi: 10.4161/onci.20068.Yatim N., Jusforgues-Saklani H., Orozco S., Schulz O., Barreira da Silva R., Reis e Sousa C., Green D.R., Oberst A., Albert M.L. RIPK1 and NF-kB signaling in dying cells determines cross-priming of CD8+ T cells. Science 2015;350:328-34. doi: 10.1126/science.aad0395.Yatim N., Jusforgues-Saklani H., Orozco S., Schulz O., Barreira da Silva R., Reis e Sousa C., Green D.R., Oberst A., Albert M.L. RIPK1 and NF-kB signaling in dying cells determines cross-priming of CD8+ T cells. Science 2015;350:328-34. doi: 10.1126/science.aad0395.Fehrenbacher L., Spira A., Ballinger M., Hida T., Gandara D.R, Cortinovis D.L., Barlesi F., Yu W., Matheny C., Ballinger M., Park K. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 3716;387:1837-46. doi: 10.1016/S0140-6736(16)00587-0.Fehrenbacher L., Spira A., Ballinger M., Hida T., Gandara D.R, Cortinovis D.L., Barlesi F., Yu W., Matheny C., Ballinger M., Park K. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 3716;387:1837-46. doi: 10.1016/S0140-6736(16)00587-0.Rosenberg J.E., Hoffman-Censits J., Powles T., Balar A.V., Necchi A., Dawson N., O'Donnell P.H., Balmanoukian A., Loriot Y., Srinivas S., Retz M.M., Grivas P., Joseph R.W., Galsky M.D., Fleming M.T., Petrylak D.P., Perez-Gracia J.L., Burris H.A., Castellano D., Canil C., Bellmunt J., Bajorin D., Nickles D., Bourgon R., Frampton G.M., Cui N., Mariathasan S., Abidoye O., Fine G.D., Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016;387:1909-20. doi: 10.1016/S0140-6736(16)00561-4.Rosenberg J.E., Hoffman-Censits J., Powles T., Balar A.V., Necchi A., Dawson N., O'Donnell P.H., Balmanoukian A., Loriot Y., Srinivas S., Retz M.M., Grivas P., Joseph R.W., Galsky M.D., Fleming M.T., Petrylak D.P., Perez-Gracia J.L., Burris H.A., Castellano D., Canil C., Bellmunt J., Bajorin D., Nickles D., Bourgon R., Frampton G.M., Cui N., Mariathasan S., Abidoye O., Fine G.D., Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016;387:1909-20. doi: 10.1016/S0140-6736(16)00561-4.Hegde P.S., Karanikas V., Evers S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res 2016;22:1865-74. doi: 10.1158/1078-0432.CCR-15-1507.Hegde P.S., Karanikas V., Evers S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res 2016;22:1865-74. doi: 10.1158/1078-0432.CCR-15-1507.Herbst R.S., Soria J.C., Kowanetz M., Fine G.D., Hamid O., Gordon M.S., Sosman J.A., McDermott D.F., Powderly J.D., Gettinger S.N., Kohrt H.E, Horn L., Lawrence D.P., Rost S., Leabman M., Xiao Y., Mokatrin A., Koeppen H., Hegde P.S., Mellman I., Chen D.S., Hodi F.S. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. A compilation of biomarker results from a series of people with cancer who were treated with the anti-PD-L1 antibody atezolizumab; this was the first study to clearly document that the expression of PD-L1 in tumours enriches for people who will respond to therapy, and that responders exhibit an influx of canonically activated T cells. Nature 2014;515:563-7. doi: 10.1038/nature14011.Herbst R.S., Soria J.C., Kowanetz M., Fine G.D., Hamid O., Gordon M.S., Sosman J.A., McDermott D.F., Powderly J.D., Gettinger S.N., Kohrt H.E, Horn L., Lawrence D.P., Rost S., Leabman M., Xiao Y., Mokatrin A., Koeppen H., Hegde P.S., Mellman I., Chen D.S., Hodi F.S. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. A compilation of biomarker results from a series of people with cancer who were treated with the anti-PD-L1 antibody atezolizumab; this was the first study to clearly document that the expression of PD-L1 in tumours enriches for people who will respond to therapy, and that responders exhibit an influx of canonically activated T cells. Nature 2014;515:563-7. doi: 10.1038/nature14011.Hamid O., Schmidt H., Nissan A., Ridolfi L., Aamdal S., Hansson J., Guida M., Hyams D.M., Gomez H., Bastholt L., Chasalow S.D., Berman D. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 2011;9:204. doi: 10.1186/1479-5876-9-204.Hamid O., Schmidt H., Nissan A., Ridolfi L., Aamdal S., Hansson J., Guida M., Hyams D.M., Gomez H., Bastholt L., Chasalow S.D., Berman D. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 2011;9:204. doi: 10.1186/1479-5876-9-204.Tumeh P.C., Harview C.L., Yearley J.H., Shintaku I.P., Taylor E.J., Robert L., Chmielowski B., Spasic M., Henry G., Ciobanu V., West A.N., Carmona M., Kivork C., Seja E., Cherry G., Gutierrez A.J., Grogan T.R., Mateus C., Tomasic G., Glaspy J.A., Emerson R.O, Robins H., Pierce R.H., Elashoff D.A., Robert C., Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568-71. doi: 10.1038/nature13954.Tumeh P.C., Harview C.L., Yearley J.H., Shintaku I.P., Taylor E.J., Robert L., Chmielowski B., Spasic M., Henry G., Ciobanu V., West A.N., Carmona M., Kivork C., Seja E., Cherry G., Gutierrez A.J., Grogan T.R., Mateus C., Tomasic G., Glaspy J.A., Emerson R.O, Robins H., Pierce R.H., Elashoff D.A., Robert C., Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568-71. doi: 10.1038/nature13954.Wistuba-Hamprecht K., Martens A., Heubach F., Romano E., Geukes Foppen M., Yuan J., Postow M., Wong P., Mallardo D., Schilling B., Di Giacomo A.M., Khammari A., Dreno B., Maio M., Schadendorf D., Ascierto P.A., Wolchok J.D., Blank C.U., Garbe C., Pawelec G., Weide B. Peripheral CD8 effector memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients. Eur J Cancer 2017;73:61-70. doi: 10.1016/j.ejca.2016.12.011.Wistuba-Hamprecht K., Martens A., Heubach F., Romano E., Geukes Foppen M., Yuan J., Postow M., Wong P., Mallardo D., Schilling B., Di Giacomo A.M., Khammari A., Dreno B., Maio M., Schadendorf D., Ascierto P.A., Wolchok J.D., Blank C.U., Garbe C., Pawelec G., Weide B. Peripheral CD8 effector memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients. Eur J Cancer 2017;73:61-70. doi: 10.1016/j.ejca.2016.12.011.Chen P.L., Roh W., Reuben A., Spencer C.N., Prieto P.A., Miller J.P., Bassett R.L., Gopalakrishnan V., Wani K., De Macedo M.P., Austin-Breneman J.L., Jiang H., Chang Q., Reddy S.M., Chen W.S., Tetzlaff M.T., Broaddus R.J., Davies M.A., Gershenwald J.E., Haydu L., Lazar A.J., Patel S.P., Hwu P., Hwu W.J., Diab A., Glitza I.C., Woodman S.E., Vence L.M., Wistuba I.I., Amaria R.N., Kwong L.N., Prieto V., Davis R.E., Ma W., Overwijk W.W., Sharpe A.H., Hu J., Futreal P.A., Blando J., Sharma P., Allison J.P., Chin L., Wargo J.A. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov 2016;6:827-37. doi: 10.1158/2159-8290.CD-15-1545.Chen P.L., Roh W., Reuben A., Spencer C.N., Prieto P.A., Miller J.P., Bassett R.L., Gopalakrishnan V., Wani K., De Macedo M.P., Austin-Breneman J.L., Jiang H., Chang Q., Reddy S.M., Chen W.S., Tetzlaff M.T., Broaddus R.J., Davies M.A., Gershenwald J.E., Haydu L., Lazar A.J., Patel S.P., Hwu P., Hwu W.J., Diab A., Glitza I.C., Woodman S.E., Vence L.M., Wistuba I.I., Amaria R.N., Kwong L.N., Prieto V., Davis R.E., Ma W., Overwijk W.W., Sharpe A.H., Hu J., Futreal P.A., Blando J., Sharma P., Allison J.P., Chin L., Wargo J.A. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov 2016;6:827-37. doi: 10.1158/2159-8290.CD-15-1545.Darvin P., Toor S.M., Sasidharan Nair V., Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 2018;50(12):1-11. doi: 10.1038/s12276-018-0191-1.Darvin P., Toor S.M., Sasidharan Nair V., Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 2018;50(12):1-11. doi: 10.1038/s12276-018-0191-1.Balatoni T., Mohos A., Papp E., Sebestyen T., Liszkay G., Olah J., Varga A., Lengyel Z., Emri G., Gaudi I., Ladanyi A. Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy. Cancer Immunol Immunother 2018;67:141-51. doi: 10.1007/s00262-017-2072-1.Balatoni T., Mohos A., Papp E., Sebestyen T., Liszkay G., Olah J., Varga A., Lengyel Z., Emri G., Gaudi I., Ladanyi A. Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy. Cancer Immunol Immunother 2018;67:141-51. doi: 10.1007/s00262-017-2072-1.Zappasodi R., Budhu S., Hellmann M.D., Postow M.A., Senbabaoglu Y., Manne S., Gasmi B., Liu C., Zhong H., Li Y., Huang A.C., Hirschhorn-Cymerman D., Panageas K.S., Wherry E.J., Merghoub T., Wolchok J.D. Non-conventional inhibitory CD4+Foxp3-PD-1hi T cells as a biomarker of immune checkpoint blockade activity. Cancer Cell 2018;33(6):1017-32. doi: 10.1016/j.ccell.2018.05.009.Zappasodi R., Budhu S., Hellmann M.D., Postow M.A., Senbabaoglu Y., Manne S., Gasmi B., Liu C., Zhong H., Li Y., Huang A.C., Hirschhorn-Cymerman D., Panageas K.S., Wherry E.J., Merghoub T., Wolchok J.D. Non-conventional inhibitory CD4+Foxp3-PD-1hi T cells as a biomarker of immune checkpoint blockade activity. Cancer Cell 2018;33(6):1017-32. doi: 10.1016/j.ccell.2018.05.009.Geng Y., Shao Y., He W., Xu Y., Chen J., Wu C., Jiang J. Prognostic role of tumor-infiltrating lymphocytes in lung cancer: A meta-analysis. Cell Physiol Biochem 2015;37:1560-71. doi: 10.1159/000438523.Geng Y., Shao Y., He W., Xu Y., Chen J., Wu C., Jiang J. Prognostic role of tumor-infiltrating lymphocytes in lung cancer: A meta-analysis. Cell Physiol Biochem 2015;37:1560-71. doi: 10.1159/000438523.Schmid P., Cruz C., Braiteh F.S., Eder J.P., Tolaney S., Kuter I., Nanda R., Chung C., Cassier P., Delord J.-P., Gordon M., Li Y., Liu B., O'Hear C., Fasso M., Molinero L., Emens L.A. Atezolizumab in metastatic TNBC (mTNBC): Long-term clinical outcomes and biomarker analyses. Cancer Res 2017;77(13):2986. doi: 10.1158/1538-7445.AM2017-2986.Schmid P., Cruz C., Braiteh F.S., Eder J.P., Tolaney S., Kuter I., Nanda R., Chung C., Cassier P., Delord J.-P., Gordon M., Li Y., Liu B., O'Hear C., Fasso M., Molinero L., Emens L.A. Atezolizumab in metastatic TNBC (mTNBC): Long-term clinical outcomes and biomarker analyses. Cancer Res 2017;77(13):2986. doi: 10.1158/1538-7445.AM2017-2986.Loi S., Schmid P., Adams S., Cortes J., Cescon D.W., Winer E.P., Toppmeyer D.L., Rugo H.S., De Laurentiis M., Nanda R., Iwata H., Awada A., Tan1 A., Wang A., Aktan G., Karantza V., Salgado R. LBA13 relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): Results from KEYNOTE-086. Ann Oncol 2017;28(Suppl. 5). doi:10.1093/annonc/mdx440.005.Loi S., Schmid P., Adams S., Cortes J., Cescon D.W., Winer E.P., Toppmeyer D.L., Rugo H.S., De Laurentiis M., Nanda R., Iwata H., Awada A., Tan1 A., Wang A., Aktan G., Karantza V., Salgado R. LBA13 relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): Results from KEYNOTE-086. Ann Oncol 2017;28(Suppl. 5). doi:10.1093/annonc/mdx440.005.Borghaei H., Paz-Ares L., Horn L., Spigel D.R., Steins M., Ready N.E., Chow L.Q., Vokes E.E., Felip E., Holgado E., Barlesi F., Kohlhaufl M., Arrieta O., Burgio M.A., Fayette J., Lena H., Poddubskaya E., Gerber D.E., Gettinger S.N., Rudin C.M., Rizvi N., Crino L., Blumenschein G.R. Jr, Antonia S.J., Dorange C., Harbison C.T., Graf Finckenstein F., Brahmer J.R. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373(17):1627-39. doi: 10.1056/NEJMoa1507643.Borghaei H., Paz-Ares L., Horn L., Spigel D.R., Steins M., Ready N.E., Chow L.Q., Vokes E.E., Felip E., Holgado E., Barlesi F., Kohlhaufl M., Arrieta O., Burgio M.A., Fayette J., Lena H., Poddubskaya E., Gerber D.E., Gettinger S.N., Rudin C.M., Rizvi N., Crino L., Blumenschein G.R. Jr, Antonia S.J., Dorange C., Harbison C.T., Graf Finckenstein F., Brahmer J.R. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373(17):1627-39. doi: 10.1056/NEJMoa1507643.Gibney G.T., Weiner L.M., Atkins M.B. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 2016;17(12):e542-e551. doi: 10.1016/S1470-2045(16)30406-5.Gibney G.T., Weiner L.M., Atkins M.B. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 2016;17(12):e542-e551. doi: 10.1016/S1470-2045(16)30406-5.Tokito T., Azuma K., Kawahara A., Ishii H., Yamada K., Matsuo N., Kinoshita T., Mizukami N., Ono H., Kage M., Hoshino T. Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Eur J Cancer 2016;55:7-14. doi: 10.1016/j.ejca.2015.11.020.Tokito T., Azuma K., Kawahara A., Ishii H., Yamada K., Matsuo N., Kinoshita T., Mizukami N., Ono H., Kage M., Hoshino T. Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Eur J Cancer 2016;55:7-14. doi: 10.1016/j.ejca.2015.11.020.Di Caro G., Bergomas F., Grizzi F., Doni A., Bianchi P., Malesci A., Laghi L., Allavena P., Mantovani A., Marchesi F. Occurrence of tertiary lymphoid tissue is associated to T-cell infiltration and predicts better prognosis in early-stage colorectal cancers. Clin Cancer Res 2014;20:2147-58. doi: 10.1158/1078-0432.CCR-13-2590.Di Caro G., Bergomas F., Grizzi F., Doni A., Bianchi P., Malesci A., Laghi L., Allavena P., Mantovani A., Marchesi F. Occurrence of tertiary lymphoid tissue is associated to T-cell infiltration and predicts better prognosis in early-stage colorectal cancers. Clin Cancer Res 2014;20:2147-58. doi: 10.1158/1078-0432.CCR-13-2590.Dong H., Strome S.E., Salomao D.R., Tamura H., Hirano F., Flies D.B., Roche P.C., Lu J., Zhu G., Tamada K., Lennon V.A., Celis E., Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793-800. doi: 10.1038/nm730.Dong H., Strome S.E., Salomao D.R., Tamura H., Hirano F., Flies D.B., Roche P.C., Lu J., Zhu G., Tamada K., Lennon V.A., Celis E., Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793-800. doi: 10.1038/nm730.Taube J.M., Young G.D., McMiller T.L., Salas J.T., Pritchard T.S., Xu H., Meeker A.K., Fan J., Cheadle C., Berger A.E., Pardoll D.M., Topalian S.L. Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade. Clin Cancer Res 2015;21:3969-76. doi: 10.1158/1078-0432.CCR-15-0244.Taube J.M., Young G.D., McMiller T.L., Salas J.T., Pritchard T.S., Xu H., Meeker A.K., Fan J., Cheadle C., Berger A.E., Pardoll D.M., Topalian S.L. Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade. Clin Cancer Res 2015;21:3969-76. doi: 10.1158/1078-0432.CCR-15-0244.Simeone E., Gentilcore G., Giannarelli D., Chen S., Salas J.T., Pritchard T.S., Xu H., Meeker A.K., Fan J., Cheadle C., Berger A.E., Pardoll D.M., Topalian S.L. Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother 2014;63:675-83. doi: 10.1007/s00262-014-1545-8.Simeone E., Gentilcore G., Giannarelli D., Chen S., Salas J.T., Pritchard T.S., Xu H., Meeker A.K., Fan J., Cheadle C., Berger A.E., Pardoll D.M., Topalian S.L. Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother 2014;63:675-83. doi: 10.1007/s00262-014-1545-8.Martens A., Wistuba-Hamprecht K., Yuan J., Postow M.A., Wong P., Capone M., Madonna G., Khammari A., Schilling B., Sucker A., Schadendorf D., Martus P., Dreno B., Ascierto P.A., Wolchok J.D., Pawelec G., Garbe C., Weide B. Increases in Absolute Lymphocytes and Circulating CD4+ and CD8+ T Cells Are Associated with Positive Clinical Outcome of Melanoma Patients Treated with Ipilimumab. Clin Cancer Res 2016;22(19):4848-58. doi: 10.1158/1078-0432.CCR-16-0249.Martens A., Wistuba-Hamprecht K., Yuan J., Postow M.A., Wong P., Capone M., Madonna G., Khammari A., Schilling B., Sucker A., Schadendorf D., Martus P., Dreno B., Ascierto P.A., Wolchok J.D., Pawelec G., Garbe C., Weide B. Increases in Absolute Lymphocytes and Circulating CD4+ and CD8+ T Cells Are Associated with Positive Clinical Outcome of Melanoma Patients Treated with Ipilimumab. Clin Cancer Res 2016;22(19):4848-58. doi: 10.1158/1078-0432.CCR-16-0249.Manola J., Atkins M., Ibrahim J., Kirkwood J. Prognostic factors in metastatic melanoma: A pooled analysis of eastern cooperative oncology group trials. J Clin Oncol 2000;18:3782-93. doi: 10.1200/JCO.2000.18.22.3782.Manola J., Atkins M., Ibrahim J., Kirkwood J. Prognostic factors in metastatic melanoma: A pooled analysis of eastern cooperative oncology group trials. J Clin Oncol 2000;18:3782-93. doi: 10.1200/JCO.2000.18.22.3782.Wang W., Yu D., Sarnaik A.A., Hall M., Morelli D., Zhang Y., Zhao X., Weber J.S. Biomarkers on melanoma patient T cells associated with ipilimumab treatment. J Transl Med 2012;10:146. doi: 10.1186/1479-5876-10-146.Wang W., Yu D., Sarnaik A.A., Hall M., Morelli D., Zhang Y., Zhao X., Weber J.S. Biomarkers on melanoma patient T cells associated with ipilimumab treatment. J Transl Med 2012;10:146. doi: 10.1186/1479-5876-10-146.Ng Tang D., Shen Y., Sun J., Wen S., Wolchok J.D., Yuan J., Allison J.P., Sharma P. Increased frequency of ICOS+CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol Res 2013;1:229-34. doi: 10.1158/2326-6066.CIR-13-0020.Ng Tang D., Shen Y., Sun J., Wen S., Wolchok J.D., Yuan J., Allison J.P., Sharma P. Increased frequency of ICOS+CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol Res 2013;1:229-34. doi: 10.1158/2326-6066.CIR-13-0020.Bendall S.C., Simonds E.F., Qiu P., Amir El-Ad., Krutzik P.O., Finck R., Bruggner R.V., Melamed R., Trejo A., Ornatsky O.I., Balderas R.S., Plevritis S.K., Sachs K., Pe'er D., Tanner S.D., Nolan G.P. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science 2011;332(6030):687-96. doi: 10.1126/science.1198704.Bendall S.C., Simonds E.F., Qiu P., Amir El-Ad., Krutzik P.O., Finck R., Bruggner R.V., Melamed R., Trejo A., Ornatsky O.I., Balderas R.S., Plevritis S.K., Sachs K., Pe'er D., Tanner S.D., Nolan G.P. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science 2011;332(6030):687-96. doi: 10.1126/science.1198704.Subrahmanyam P.B., Dong Z., Gusenleitner D., Giobbie-Hurder A., Severgnini M., Zhou J., Manos M., Eastman L.M., Maecker H.T., Hodi F.S. Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients. J Immunother Cancer 2018;6(1):18. doi: 10.1186/s40425-018-0328-8.Subrahmanyam P.B., Dong Z., Gusenleitner D., Giobbie-Hurder A., Severgnini M., Zhou J., Manos M., Eastman L.M., Maecker H.T., Hodi F.S. Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients. J Immunother Cancer 2018;6(1):18. doi: 10.1186/s40425-018-0328-8.de Coana Y.P., Wolodarski M., Poschke I., Yoshimoto Y., Yang Y., Nystrom M., Edback U., Eghyazi Brage S., Lundqvist A., Masucci G.V., Hansson J., Kiessling R. Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma. Oncotarget 2017;8:21539-53. doi: 10.18632/oncotarget.15368.de Coana Y.P., Wolodarski M., Poschke I., Yoshimoto Y., Yang Y., Nystrom M., Edback U., Eghyazi Brage S., Lundqvist A., Masucci G.V., Hansson J., Kiessling R. Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma. Oncotarget 2017;8:21539-53. doi: 10.18632/oncotarget.15368.Park J.A., Cheung N.V. Limitations and opportunities for immune checkpoint inhibitors in pediatric malignancies. Cancer Treat Rev 2017;58:22-33. doi: 10.1016/j.ctrv.2017.05.006.Park J.A., Cheung N.V. Limitations and opportunities for immune checkpoint inhibitors in pediatric malignancies. Cancer Treat Rev 2017;58:22-33. doi: 10.1016/j.ctrv.2017.05.006.van Dam L.S., de Zwart V.M., Meyer-Wentrup F.A. The role of programmed cell death-1 (PD-1) and its ligands in pediatric cancer. Pediatr Blood Cancer 2015;62(2):190-7. doi: 10.1002/pbc.25284.van Dam L.S., de Zwart V.M., Meyer-Wentrup F.A. The role of programmed cell death-1 (PD-1) and its ligands in pediatric cancer. Pediatr Blood Cancer 2015;62(2):190-7. doi: 10.1002/pbc.25284.Lussier D.M., O'Neill L., Nieves L.M., McAfee M.S., Holechek S.A., Collins A.W., Dickman P., Jacobsen J., Hingorani P., Blattman J.N. Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD1/PD-L1 interactions. J Immunother 2015;38(3):96-106. doi: 10.1097/CJI.0000000000000065.Lussier D.M., O'Neill L., Nieves L.M., McAfee M.S., Holechek S.A., Collins A.W., Dickman P., Jacobsen J., Hingorani P., Blattman J.N. Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD1/PD-L1 interactions. J Immunother 2015;38(3):96-106. doi: 10.1097/CJI.0000000000000065.Karim L.A., Wang P., de Guzman J., Higgins B., Chahine J., Sheehan C., Kallakury B., Ross J.S. PDL1 protein expression and tumor mutation burden in hematologic malignancies: correlation with Hodgkin and high grade lymphoma. Cancer Res 2017;77(13 Suppl):3724.Karim L.A., Wang P., de Guzman J., Higgins B., Chahine J., Sheehan C., Kallakury B., Ross J.S. PDL1 protein expression and tumor mutation burden in hematologic malignancies: correlation with Hodgkin and high grade lymphoma. Cancer Res 2017;77(13 Suppl):3724.Shi L., Chen S., Yang L., Li Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol 2013;6(1):74. doi: 10.1186/1756-8722-6-74.Shi L., Chen S., Yang L., Li Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol 2013;6(1):74. doi: 10.1186/1756-8722-6-74.Andorsky D.J., Yamada R.E., Said J., Pinkus G.S., Betting D.J., Timmerman J.M. Programmed death ligand 1 is expressed by nonHodgkin lymphomas and inhibits the activity of tumorassociated T cells. Clin Cancer Res 2011;17(13):4232-44. doi: 10.1158/1078-0432.CCR-10-2660.Andorsky D.J., Yamada R.E., Said J., Pinkus G.S., Betting D.J., Timmerman J.M. Programmed death ligand 1 is expressed by nonHodgkin lymphomas and inhibits the activity of tumorassociated T cells. Clin Cancer Res 2011;17(13):4232-44. doi: 10.1158/1078-0432.CCR-10-2660.Yao Y., Tao R., Wang X., Wang Y., Mao Y., Zhou L.F. B7-H1 is correlated with malignancy-grade gliomas but is not expressed exclusively on tumor stem-like cells. Neuro Oncol 2009;11(6):757-66. doi: 10.1215/15228517-2009-014.Yao Y., Tao R., Wang X., Wang Y., Mao Y., Zhou L.F. B7-H1 is correlated with malignancy-grade gliomas but is not expressed exclusively on tumor stem-like cells. Neuro Oncol 2009;11(6):757-66. doi: 10.1215/15228517-2009-014.Wintterle S., Schreiner B., Mitsdoerffer M., Schneider D., Chen L., Meyermann R., Weller M., Wiendl H. Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res 2003;63(21):7462-7. PMID: 14612546.Wintterle S., Schreiner B., Mitsdoerffer M., Schneider D., Chen L., Meyermann R., Weller M., Wiendl H. Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res 2003;63(21):7462-7. PMID: 14612546.Pinto N., Park J.R., Murphy E., Yearley J., McClanahan T., Annamalai L., Hawkins D.S., Rudzinski E.R. Patterns of PD-1, PD-L1, and PD-L2 expression in pediatric solid tumors. Pediatr Blood Cancer 2017;64(11). doi: 10.1002/pbc.26613.Pinto N., Park J.R., Murphy E., Yearley J., McClanahan T., Annamalai L., Hawkins D.S., Rudzinski E.R. Patterns of PD-1, PD-L1, and PD-L2 expression in pediatric solid tumors. Pediatr Blood Cancer 2017;64(11). doi: 10.1002/pbc.26613.Routh J.C., Ashley R.A., Sebo T.J., Lohse C.M., Husmann D.A., Kramer S.A., Kwon E.D. B7-H1 expression in Wilms tumor: correlation with tumor biology and disease recurrence. J Urol 2008;179:1954-9. doi: 10.1016/j.juro.2008.01.056.Routh J.C., Ashley R.A., Sebo T.J., Lohse C.M., Husmann D.A., Kramer S.A., Kwon E.D. B7-H1 expression in Wilms tumor: correlation with tumor biology and disease recurrence. J Urol 2008;179:1954-9. doi: 10.1016/j.juro.2008.01.056.Bertolini G., Bergamaschi L., Ferrari A., Renne S.L, Collini P., Gardelli C., Barisella M., Centonze G., Chiaravalli S., Paolino C., Milione M., Massimino M., Casanova M., Gasparini P. PD-L1 assessment in pediatric rhabdomyosarcoma: a pilot study. BMC Cancer 2018;18(1):652. doi: 10.1186/s12885-018-4554-8.Bertolini G., Bergamaschi L., Ferrari A., Renne S.L, Collini P., Gardelli C., Barisella M., Centonze G., Chiaravalli S., Paolino C., Milione M., Massimino M., Casanova M., Gasparini P. PD-L1 assessment in pediatric rhabdomyosarcoma: a pilot study. BMC Cancer 2018;18(1):652. doi: 10.1186/s12885-018-4554-8.Davis K.L., Fox E., Merchant M.S., Reid J.M., Kudgus R.A., Liu X., Minard C.G., Voss S., Berg S.L., Weigel B.J., Mackal C.L. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): A multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol 2020;21:541-50. doi: 10.1016/S1470-2045(20)30023-1.Davis K.L., Fox E., Merchant M.S., Reid J.M., Kudgus R.A., Liu X., Minard C.G., Voss S., Berg S.L., Weigel B.J., Mackal C.L. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): A multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol 2020;21:541-50. doi: 10.1016/S1470-2045(20)30023-1.Dondero A., Pastorino F., Della Chiesa M., Corrias M.V., Morandi F., Pistoia V., Olive D., Bellora F., Locatelli F., Castellano A., Moretta L., Bottino C., Castriconi R. PD-L1 expression in metastatic neuroblastoma as an additional mechanism for limiting immune surveillance. Oncoimmunol 2016;5:e1064578. doi: 10.1080/2162402X.2015.1064578.Dondero A., Pastorino F., Della Chiesa M., Corrias M.V., Morandi F., Pistoia V., Olive D., Bellora F., Locatelli F., Castellano A., Moretta L., Bottino C., Castriconi R. PD-L1 expression in metastatic neuroblastoma as an additional mechanism for limiting immune surveillance. Oncoimmunol 2016;5:e1064578. doi: 10.1080/2162402X.2015.1064578.Siebert N., Zumpe M., Juttner M., Troschke-Meurer S., Lode H. PD-1 blockade augments anti-neuroblastoma immune response induced by anti-GD2 antibody ch14.18/CHO. Oncoimmunol 2017;6:e1343775. doi: 10.1080/2162402X.2017.1343775.Siebert N., Zumpe M., Juttner M., Troschke-Meurer S., Lode H. PD-1 blockade augments anti-neuroblastoma immune response induced by anti-GD2 antibody ch14.18/CHO. Oncoimmunol 2017;6:e1343775. doi: 10.1080/2162402X.2017.1343775.Ehlert K., Hansjuergens I., Zinke A., Otto S., Siebert N., Henze G., Lode H. Nivolumab and dinutuximab beta in two patients with refractory neuroblastoma. J Immunother Cancer 2020;8(1):e000540. doi: 10.1136/jitc-2020-000540.Ehlert K., Hansjuergens I., Zinke A., Otto S., Siebert N., Henze G., Lode H. Nivolumab and dinutuximab beta in two patients with refractory neuroblastoma. J Immunother Cancer 2020;8(1):e000540. doi: 10.1136/jitc-2020-000540.Lucchesi M., Sardi I., Puppo G., Chella A., Favre C. The dawn of “immune-revolution” in children: early experiences with checkpoint inhibitors in childhood malignancies. Cancer Chemother Pharmacol 2017;80(6):1047-53. doi: 10.1007/s00280-017-3450-2.Lucchesi M., Sardi I., Puppo G., Chella A., Favre C. The dawn of “immune-revolution” in children: early experiences with checkpoint inhibitors in childhood malignancies. Cancer Chemother Pharmacol 2017;80(6):1047-53. doi: 10.1007/s00280-017-3450-2.Merchant M.S., Wright M., Baird K., Wexler L.H., Rodriguez-Galindo C., Bernstein D., Delbrook C., Lodish M., Bishop R., Wolchok J.D., Streicher H., Mackall C.L. Phase I clinical trial of ipilimumab in pediatric patients with advanced solid tumors. Clin Cancer Res 2016;22(6):1364-70. doi: 10.1158/1078-0432.CCR-15-0491.Merchant M.S., Wright M., Baird K., Wexler L.H., Rodriguez-Galindo C., Bernstein D., Delbrook C., Lodish M., Bishop R., Wolchok J.D., Streicher H., Mackall C.L. Phase I clinical trial of ipilimumab in pediatric patients with advanced solid tumors. Clin Cancer Res 2016;22(6):1364-70. doi: 10.1158/1078-0432.CCR-15-0491.van der Woude L.L., Gorris M.A.J., Halilovic A., Figdor C.G., de Vries I.J.M. Migrating into the tumor: a roadmap for T cells. Trends Cancer 2017;3:797-808. doi: 10.1016/j.trecan.2017.09.006.van der Woude L.L., Gorris M.A.J., Halilovic A., Figdor C.G., de Vries I.J.M. Migrating into the tumor: a roadmap for T cells. Trends Cancer 2017;3:797-808. doi: 10.1016/j.trecan.2017.09.006.Awad R.M., de Vlaeminck Y., Maebe J., Goyvaerts C., Breckpot K. Turn back the TIMe: targeting tumor infiltrating myeloid cells to revert cancer progression. Front Immunol 2018;9:1977. doi: 10.3389/fimmu.2018.01977.Awad R.M., de Vlaeminck Y., Maebe J., Goyvaerts C., Breckpot K. Turn back the TIMe: targeting tumor infiltrating myeloid cells to revert cancer progression. Front Immunol 2018;9:1977. doi: 10.3389/fimmu.2018.01977.

The authors declare that there are no conflicts of interest present.