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

Kevin Litchfield, James L. Reading, Clare Puttick, Krupa Thakkar, Chris Abbosh, Robert Bentham, Thomas B.K. Watkins, Rachel Rosenthal, Dhruva Biswas, Andrew Rowan, Emilia Lim, Maise Al Bakir, Virginia Turati, José Afonso Guerra-Assunção, Lucia Conde, Andrew J.S. Furness, Sunil Kumar Saini, Sine R. Hadrup, Javier Herrero, Se Hoon LeePeter Van Loo, Tariq Enver, James Larkin, Matthew D. Hellmann, Samra Turajlic, Sergio A. Quezada*, Nicholas McGranahan, Charles Swanton

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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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.

Original languageEnglish
JournalCELL
Volume184
Issue number3
Pages (from-to)596-614
ISSN0092-8674
DOIs
Publication statusPublished - 2021

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