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

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journal contribution
posted on 31.03.2021, 10:45 by Kevin Litchfield, James L Reading, Clare Puttick, Krupa Thakkar, Chris Abbosh, Robert Bentham, Thomas BK Watkins, Rachel Rosenthal, Dhruva Biswas, Andrew Rowan, Emilia Lim, Maise Al Bakir, Virginia Turati, José Afonso Guerra-Assunção, Lucia Conde, Andrew JS Furness, Sunil Kumar Saini, Sine R Hadrup, Javier Herrero, Se-Hoon Lee, Peter Van Loo, Tariq Enver, James Larkin, Matthew D Hellmann, Samra Turajlic, Sergio A Quezada, Nicholas McGranahan, Charles Swanton
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.

Funding

Crick (Grant ID: 10988, Grant title: Turajlic FC001988) Crick (Grant ID: 10202, Grant title: Van Loo FC001202) Crick (Grant ID: 10169, Grant title: Swanton FC001169) European Research Council (Grant ID: 835297 - PROTEUS, Grant title: ERC 835297 - PROTEUS) Novo Nordisk UK Research Foundation (Grant ID: NNF15OC0016584, Grant title: NovoNordisk Foundation 16584) Cancer Research UK (Grant ID: 18176, Grant title: CRUK C50947/A18176) European Research Council (Grant ID: 617844 - THESEUS, Grant title: ERC 617844 - THESEUS) Medical Research Council (Grant ID: MC_PC_17179, Grant title: CiC 2017: Crick Idea to Innovation (i2i))

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