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

被引：540

作者：

Litchfield, Kevin ^{[1
,3
]}

Reading, James L. ^{[2
,3
]}

Puttick, Clare ^{[1
]}

Thakkar, Krupa ^{[1
,3
]}

Abbosh, Chris ^{[3
]}

Bentham, Robert ^{[3
]}

Watkins, Thomas B. K. ^{[1
]}

Rosenthal, Rachel ^{[1
]}

Biswas, Dhruva ^{[1
]}

Rowan, Andrew ^{[1
]}

Lim, Emilia ^{[1
]}

Al Bakir, Maise ^{[1
]}

Turati, Virginia ^{[4
]}

Guerra-Assuncao, Jose Afonso ^{[5
]}

Conde, Lucia ^{[5
]}

Furness, Andrew J. S. ^{[6
]}

Saini, Sunil Kumar ^{[7
]}

Hadrup, Sine R. ^{[7
]}

Herrero, Javier ^{[5
]}

Lee, Se-Hoon ^{[8
,9
]}

Van Loo, Peter ^{[10
]}

Enver, Tariq ^{[4
]}

Larkin, James ^{[6
]}

Hellmann, Matthew D. ^{[11
,12
]}

Turajlic, Samra ^{[6
,13
]}

Quezada, Sergio A. ^{[2
,3
]}

McGranahan, Nicholas ^{[3
]}

Swanton, Charles ^{[1
,3
]}

机构：

[1] Francis Crick Inst, Canc Evolut & Genome Instabil Lab, 1 Midland Rd, London NW1 1AT, England

[2] UCL, Res Dept Hematol, Canc Immunol Unit, Canc Inst, Paul Gorman Bldg,72 Huntley St, London WC1E 6BT, England

[3] UCL, Canc Res UK Lung Canc Ctr Excellence, Canc Inst, Paul Gorman Bldg,72 Huntley St, London WC1E 6BT, England

[4] UCL, Canc Inst, Stem Cell Grp, London WC1E 6DD, England

[5] UCL, Bill Lyons Informat Ctr, Canc Inst, Paul OGorman Bldg,72 Huntley St, London WC1E 6BT, England

[6] Royal Marsden NHS Fdn Trust, Renal & Skin Units, London SW3 6JJ, England

[7] Tech Univ Denmark, Dept Hlth Technol, Copenhagen, Denmark

[8] Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Dept Hlth Sci & Technol, Seoul, South Korea

[9] Sungkyunkwan Univ, Samsung Med Ctr, Dept Med, Div Hematol Oncol,Sch Med, Seoul, South Korea

[10] Francis Crick Inst, Canc Genom Lab, 1 Midland Rd, London NW1 1AT, England

[11] Mem Sloan Kettering Canc Ctr, Weill Cornell Med Coll, Dept Med, Thorac Oncol Serv,Div Solid Tumor Oncol, 885 2nd Ave, New York, NY 10017 USA

[12] Parker Ctr Canc Immunotherapy, 885 2nd Ave, New York, NY 10017 USA

[13] Francis Crick Inst, Canc Dynam Lab, 1 Midland Rd, London NW1 1AT, England

来源：

CELL | 2021年 / 184卷 / 03期

基金：

新加坡国家研究基金会; 欧盟地平线“2020”; 欧洲研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

MHC CLASS-I; PD-1; BLOCKADE; COPY-NUMBER; LUNG-CANCER; MUTATIONAL PROCESSES; SOMATIC MUTATIONS; CLINICAL-RESPONSE; CTLA-4; BLADDER-CANCER; RESISTANCE;

D O I：

10.1016/j.cell.2021.01.002

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：596 / +

页数：33

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