Through multi-omic analysis of multi-region and longitudinal tumor biopsies taken pre- and post-treatment from 15 patients (5 responders) with ccRCC, Au et al. evaluated genomic and TME features associated with responsiveness to anti-PD-1. Responders had more similarity in TCR repertoire between timepoints and heightened expansion, indicating a greater degree of maintenance of pre-existing, tumor-specific intratumoral T cells than non-responders. Neither TMB nor expansion of novel T cell clones correlated with response. Expression of CD3E, CD8A, GZMB, and TCF7 were higher, and pathways of immune-activation and TCR signaling were enriched in responders.
Contributed by Margot O’Toole
ABSTRACT: 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.
Author Info: (1) 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. (2) Renal and Skin
Author Info: (1) 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. (2) 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. (3) 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. (4) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK. (5) Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK. (6) Retroviral Immunology, The Francis Crick Institute, London NW1 1AT, UK. (7) Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London NW1 1AT, UK. (8) Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden Hospital, London SW3 6JJ, UK. (9) Department of Pathology, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (10) Department of Urology, the Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (11) Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (12) 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. (13) Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London WC1E 6DD, UK. (14) Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. (15) Translational Immune Oncology Lab, Centre for Molecular Pathology, The Royal Marsden Hospital, Sutton SM2 5PT, UK. (16) Department of Pathology, Cruces University Hospital, Biocruces-Bizkaia Institute, 48903 Barakaldo, Bizkaia, Spain. (17) Department of Cellular Pathology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK. (18) 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. (19) Division of Research, Peter MacCallum Cancer Centre, Melbourne VIC 300, Australia; Department of Pathology, GZA-ZNA Hospitals, Wilrijk, Antwerp, Belgium. (20) 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. (21) Division of Infection and Immunity, University College London, London WC1E 6BT, UK; University College London Cancer Institute, London WC1E 6DD, UK. (22) 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. (23) 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. (24) 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.
