TY - JOUR
T1 - Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition
AU - Litchfield, Kevin
AU - Reading, James L.
AU - Puttick, Clare
AU - Thakkar, Krupa
AU - Abbosh, Chris
AU - Bentham, Robert
AU - Watkins, Thomas B.K.
AU - Rosenthal, Rachel
AU - Biswas, Dhruva
AU - Rowan, Andrew
AU - Lim, Emilia
AU - Al Bakir, Maise
AU - Turati, Virginia
AU - Guerra-Assunção, José Afonso
AU - Conde, Lucia
AU - Furness, Andrew J.S.
AU - Saini, Sunil Kumar
AU - Hadrup, Sine R.
AU - Herrero, Javier
AU - Lee, Se Hoon
AU - Van Loo, Peter
AU - Enver, Tariq
AU - Larkin, James
AU - Hellmann, Matthew D.
AU - Turajlic, Samra
AU - Quezada, Sergio A.
AU - McGranahan, Nicholas
AU - Swanton, Charles
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1016/j.cell.2021.01.002
DO - 10.1016/j.cell.2021.01.002
M3 - Journal article
C2 - 33508232
AN - SCOPUS:85100246027
SN - 0092-8674
VL - 184
SP - 596
EP - 614
JO - Cell
JF - Cell
IS - 3
ER -
