Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.

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.

Cancer cell. 2021 Oct 26 [Epub ahead of print]

Lewis Au, Emine Hatipoglu, Marc Robert de Massy, Kevin Litchfield, Gordon Beattie, Andrew Rowan, Desiree Schnidrig, Rachael Thompson, Fiona Byrne, Stuart Horswell, Nicos Fotiadis, Steve Hazell, David Nicol, Scott T C Shepherd, Annika Fendler, Robert Mason, Lyra Del Rosario, Kim Edmonds, Karla Lingard, Sarah Sarker, Mary Mangwende, Eleanor Carlyle, Jan Attig, Kroopa Joshi, Imran Uddin, Pablo D Becker, Mariana Werner Sunderland, Ayse Akarca, Ignazio Puccio, William W Yang, Tom Lund, Kim Dhillon, Marcos Duran Vasquez, Ehsan Ghorani, Hang Xu, Charlotte Spencer, José I López, Anna Green, Ula Mahadeva, Elaine Borg, Miriam Mitchison, David A Moore, Ian Proctor, Mary Falzon, Lisa Pickering, Andrew J S Furness, James L Reading, Roberto Salgado, Teresa Marafioti, Mariam Jamal-Hanjani, PEACE Consortium , George Kassiotis, Benny Chain, James Larkin, Charles Swanton, Sergio A Quezada, Samra Turajlic, TRACERx Renal Consortium

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., 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., 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., Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK., Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK., Retroviral Immunology, The Francis Crick Institute, London NW1 1AT, UK., Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London NW1 1AT, UK., Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden Hospital, London SW3 6JJ, UK., Department of Pathology, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK., Department of Urology, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK., 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; Division of Infection and Immunity, University College London, London WC1E 6BT, UK., Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK., Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK., Translational Immune Oncology Lab, Centre for Molecular Pathology, The Royal Marsden Hospital, Sutton SM2 5PT, UK., Department of Pathology, Cruces University Hospital, Biocruces-Bizkaia Institute, 48903 Barakaldo, Bizkaia, Spain., Department of Cellular Pathology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK., 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., Division of Research, Peter MacCallum Cancer Centre, Melbourne VIC 300, Australia; Department of Pathology, GZA-ZNA Hospitals, Wilrijk, Antwerp, Belgium., 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., Division of Infection and Immunity, University College London, London WC1E 6BT, UK; 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; 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., 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: ., 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: .