Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

• Published in: Cell Vol. 184; no. 3; pp. 596 - 614.e14
• Main Authors: Litchfield, Kevin, Reading, James L., Puttick, Clare, Thakkar, Krupa, Abbosh, Chris, Bentham, Robert, Watkins, Thomas B.K., Rosenthal, Rachel, Biswas, Dhruva, Rowan, Andrew, Lim, Emilia, Al Bakir, Maise, Turati, Virginia, Guerra-Assunção, José Afonso, Conde, Lucia, Furness, Andrew J.S., Saini, Sunil Kumar, Hadrup, Sine R., Herrero, Javier, Lee, Se-Hoon, Van Loo, Peter, Enver, Tariq, Larkin, James, Hellmann, Matthew D., Turajlic, Samra, Quezada, Sergio A., McGranahan, Nicholas, Swanton, Charles
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.02.2021; Cell Press
• Subjects: amino acids; bioinformatics; biomarkers; Biomarkers, Tumor - metabolism; CD8 Antigens - metabolism; checkpoint inhibitors; Chemokine CXCL13 - metabolism; Chromosomes, Human, Pair 9 - genetics; clonal TMB; Cohort Studies; CXCL9; Cyclin D1 - genetics; divergent evolution; DNA Copy Number Variations - genetics; epitopes; Exome - genetics; Gene Amplification; Humans; hydrophobicity; Immune Checkpoint Inhibitors - pharmacology; Immune Evasion - drug effects; immunogenicity; immunotherapy; meta-analysis; Multivariate Analysis; mutation; Mutation - genetics; neoantigen; neoplasms; Neoplasms - immunology; Neoplasms - pathology; Polymorphism, Single Nucleotide - genetics; Receptors, CCR5 - metabolism; RNA; sequence analysis; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; transcriptomics; Tumor Burden - genetics; neoantigen; mutation; clonal TMB; CXCL9; biomarkers; immunotherapy; meta-analysis; immunogenicity; checkpoint inhibitors
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2021.01.002

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. [Display omitted] •Large-scale meta-analysis of >1,000 CPI-treated cases with exome/transcriptome data•Clonal TMB and CXCL9/CXCL13 expression are the strongest predictors of CPI response•A multivariable predictor of CPI response significantly outperforms TMB•9q34 loss and CCND1 amplification are additional determinants of CPI response A whole-exome and transcriptome meta-analysis of over 1,000 patients treated with immune checkpoint blockade across seven tumor types highlights the potential of multivariable prediction models that consider both tumor- and T-cell-intrinsic mechanisms of response.