Litchfield, Reading, and Puttick et al. performed a meta-analysis of exome and transcriptome data across >1000 patients and tumor types, treated with immune checkpoint inhibitors (CPI), to identify tumor- and T cell- intrinsic predictors of response. Clonal tumor mutational burden (TMB), followed by TMB and CXCL9 were the best predictors of response, whereas subclonal TMB, somatic copy alterations, and LOH at HLA locus had no association. A trained multivariable predictor outperformed TMB. Loss of 9q34 was predictive of response, and amplification of CCND1 was predictive of resistance to CPI. CXCR3 and CXCL13 were T cell-intrinsic markers for CPI response.
Contributed by Shishir Pant
ABSTRACT: Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity.
Author Info: (1) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, Univer
Author Info: (1) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. (2) Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. (3) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (4) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. (5) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. (6) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. (7) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (8) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (9) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (10) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (11) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (12) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (13) Stem Cell Group, Cancer Institute, University College London, London WC1E 6DD, UK. (14) Bill Lyons Informatics Centre, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. (15) Bill Lyons Informatics Centre, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. (16) Renal and Skin Units, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (17) Department of Health Technology, Technical University of Denmark, Copenhagen, Denmark. (18) Department of Health Technology, Technical University of Denmark, Copenhagen, Denmark. (19) Bill Lyons Informatics Centre, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. (20) Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. (21) Cancer Genomics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (22) Stem Cell Group, Cancer Institute, University College London, London WC1E 6DD, UK. (23) Renal and Skin Units, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (24) Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, and Parker Center for Cancer Immunotherapy, 885 2nd Avenue, New York, NY 10017, USA. (25) Renal and Skin Units, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; Cancer Dynamics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (26) Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. Electronic address: s.quezada@ucl.ac.uk. (27) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. Electronic address: nicholas.mcgranahan.10@ucl.ac.uk. (28) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. Electronic address: charles.swanton@crick.ac.uk.
