Journal article
Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition
University College London1
The Francis Crick Institute2
Royal Marsden NHS Foundation Trust3
Department of Health Technology, Technical University of Denmark4
Experimental & Translational Immunology, Department of Health Technology, Technical University of Denmark5
T-Cells and Cancer, Experimental & Translational Immunology, Department of Health Technology, Technical University of Denmark6
Sungkyunkwan University7
Cornell University8
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.
Language: | English |
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Publisher: | Cell Press |
Year: | 2021 |
Pages: | 596-614 |
ISSN: | 10974172 and 00928674 |
Types: | Journal article |
DOI: | 10.1016/j.cell.2021.01.002 |
ORCIDs: | 0000-0001-5381-978X , 0000-0003-0487-8980 , 0000-0001-9141-5188 , Saini, Sunil Kumar , 0000-0003-0292-1949 , 0000-0001-5569-9523 , 0000-0002-2670-9777 , 0000-0002-9763-1700 and Hadrup, Sine R. |
Biomarkers, Tumor CD8 Antigens CXCL9 Chemokine CXCL13 Chromosomes, Human, Pair 9 Cohort Studies Cyclin D1 DNA Copy Number Variations Exome Gene Amplification Humans Immune Checkpoint Inhibitors Immune Evasion Multivariate Analysis Mutation Neoplasms Polymorphism, Single Nucleotide Receptors, CCR5 T-Lymphocytes Tumor Burden biomarkers checkpoint inhibitors clonal TMB immunogenicity immunotherapy meta-analysis mutation neoantigen