Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition.
Date
2021-02-04ICR Author
Author
Litchfield, K
Reading, JL
Puttick, C
Thakkar, K
Abbosh, C
Bentham, R
Watkins, TBK
Rosenthal, R
Biswas, D
Rowan, A
Lim, E
Al Bakir, M
Turati, V
Guerra-Assunção, JA
Conde, L
Furness, AJS
Saini, SK
Hadrup, SR
Herrero, J
Lee, S-H
Van Loo, P
Enver, T
Larkin, J
Hellmann, MD
Turajlic, S
Quezada, SA
McGranahan, N
Swanton, C
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
CXCL9
biomarkers
checkpoint inhibitors
clonal TMB
immunogenicity
immunotherapy
meta-analysis
mutation
neoantigen
Biomarkers, Tumor
CD8 Antigens
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
Research team
Skin Unit
Language
eng
Date accepted
2021-01-04
License start date
2021-02-04
Citation
Cell, 2021, 184 (3), pp. 596 - 614.e14
Publisher
CELL PRESS