PMID- 34715028 OWN - NLM STAT- MEDLINE VI - 39 IP - 11 TI - Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma. PG - 1497-1518.e11 CI - Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Cancer Cell JT - Cancer cell JID - 101130617 IS - 1878-3686 (Electronic) LID - S1535-6108(21)00543-2 [pii] LID - 10.1016/j.ccell.2021.10.001 [doi] FAU - Au, Lewis AU - Au L AD - Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Hatipoglu, Emine AU - Hatipoglu E AD - Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK. FAU - Robert de Massy, Marc AU - Robert de Massy M AD - Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK. FAU - Litchfield, Kevin AU - Litchfield K AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK. FAU - Beattie, Gordon AU - Beattie G AD - Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK. FAU - Rowan, Andrew AU - Rowan A AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK. FAU - Schnidrig, Desiree AU - Schnidrig D AD - Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK. FAU - Thompson, Rachael AU - Thompson R AD - Retroviral Immunology, The Francis Crick Institute, London NW1 1AT, UK. FAU - Byrne, Fiona AU - Byrne F AD - Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK. FAU - Horswell, Stuart AU - Horswell S AD - Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London NW1 1AT, UK. FAU - Fotiadis, Nicos AU - Fotiadis N AD - Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden Hospital, London SW3 6JJ, UK. FAU - Hazell, Steve AU - Hazell S AD - Department of Pathology, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Nicol, David AU - Nicol D AD - Department of Urology, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Shepherd, Scott T C AU - Shepherd STC AD - Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Fendler, Annika AU - Fendler A AD - Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK. FAU - Mason, Robert AU - Mason R AD - Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Del Rosario, Lyra AU - Del Rosario L AD - Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Edmonds, Kim AU - Edmonds K AD - Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Lingard, Karla AU - Lingard K AD - Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Sarker, Sarah AU - Sarker S AD - Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Mangwende, Mary AU - Mangwende M AD - Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Carlyle, Eleanor AU - Carlyle E AD - Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Attig, Jan AU - Attig J AD - Retroviral Immunology, The Francis Crick Institute, London NW1 1AT, UK. FAU - Joshi, Kroopa AU - Joshi K AD - Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK. FAU - Uddin, Imran AU - Uddin I AD - Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK; Division of Infection and Immunity, University College London, London WC1E 6BT, UK. FAU - Becker, Pablo D AU - Becker PD AD - Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK. FAU - Sunderland, Mariana Werner AU - Sunderland MW AD - Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK. FAU - Akarca, Ayse AU - Akarca A AD - Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. FAU - Puccio, Ignazio AU - Puccio I AD - Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. FAU - Yang, William W AU - Yang WW AD - Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. FAU - Lund, Tom AU - Lund T AD - Translational Immune Oncology Lab, Centre for Molecular Pathology, The Royal Marsden Hospital, Sutton SM2 5PT, UK. FAU - Dhillon, Kim AU - Dhillon K AD - Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. FAU - Vasquez, Marcos Duran AU - Vasquez MD AD - Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK. FAU - Ghorani, Ehsan AU - Ghorani E AD - Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK. FAU - Xu, Hang AU - Xu H AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK. FAU - Spencer, Charlotte AU - Spencer C AD - Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK. FAU - López, José I AU - López JI AD - Department of Pathology, Cruces University Hospital, Biocruces-Bizkaia Institute, 48903 Barakaldo, Bizkaia, Spain. FAU - Green, Anna AU - Green A AD - Department of Cellular Pathology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK. FAU - Mahadeva, Ula AU - Mahadeva U AD - Department of Cellular Pathology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK. FAU - Borg, Elaine AU - Borg E AD - Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. FAU - Mitchison, Miriam AU - Mitchison M AD - Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. FAU - Moore, David A AU - Moore DA AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK; Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. FAU - Proctor, Ian AU - Proctor I AD - Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. FAU - Falzon, Mary AU - Falzon M AD - Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. FAU - Pickering, Lisa AU - Pickering L AD - Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Furness, Andrew J S AU - Furness AJS AD - Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Reading, James L AU - Reading JL AD - Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK. FAU - Salgado, Roberto AU - Salgado R AD - Division of Research, Peter MacCallum Cancer Centre, Melbourne VIC 300, Australia; Department of Pathology, GZA-ZNA Hospitals, Wilrijk, Antwerp, Belgium. FAU - Marafioti, Teresa AU - Marafioti T AD - Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. FAU - Jamal-Hanjani, Mariam AU - Jamal-Hanjani M AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Metastasis Laboratory, University College London Cancer Institute, London WC1E 6DD, UK; Department of Medical Oncology, University College London Hospitals, London NW1 2BU, UK. CN - PEACE Consortium FAU - Kassiotis, George AU - Kassiotis G AD - Retroviral Immunology, The Francis Crick Institute, London NW1 1AT, UK. FAU - Chain, Benny AU - Chain B AD - Division of Infection and Immunity, University College London, London WC1E 6BT, UK; University College London Cancer Institute, London WC1E 6DD, UK. FAU - Larkin, James AU - Larkin J AD - Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. FAU - Swanton, Charles AU - Swanton C AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Medical Oncology, University College London Hospitals, London NW1 2BU, UK; University College London Cancer Institute, London WC1E 6DD, UK. FAU - Quezada, Sergio A AU - Quezada SA AD - Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK. Electronic address: s.quezada@ucl.ac.uk. FAU - Turajlic, Samra AU - Turajlic S AD - Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. Electronic address: samra.turajlic@crick.ac.uk. CN - TRACERx Renal Consortium IS - 1535-6108 (Linking) RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (Receptors, Antigen, T-Cell) RN - 31YO63LBSN (Nivolumab) SB - IM MH - CD8-Positive T-Lymphocytes MH - Carcinoma, Renal Cell/*drug therapy/genetics MH - Clinical Trials, Phase II as Topic MH - *Drug Resistance, Neoplasm MH - Endogenous Retroviruses/genetics MH - Gene Expression Profiling/methods MH - Genomics/methods MH - Humans MH - Immune Checkpoint Inhibitors/*administration & dosage/pharmacology MH - Kidney Neoplasms/*drug therapy/genetics MH - Nivolumab/*administration & dosage/pharmacology MH - Prospective Studies MH - Receptors, Antigen, T-Cell/*genetics MH - Sequence Analysis, RNA MH - Single-Cell Analysis MH - Tumor Escape MH - Tumor Microenvironment MH - Exome Sequencing OTO - NOTNLM OT - T cell receptor OT - TCR clonal maintenance OT - TCR clonal replacement OT - anti-PD-1 OT - autopsy OT - clear cell renal cell carcinoma OT - human endogenous retrovirus OT - multiregion OT - nivolumab PMC - PMC8599450 DCOM- 20220105 LR - 20240210 DP - 20211108 DEP - 20211028 AB - ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.