期刊
CELL
卷 184, 期 3, 页码 596-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2021.01.002
关键词
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资金
- UK Medical Research Council [MR/P014712/1, FC001202, FC001169]
- Rosetrees Trust [A2204, A1388]
- Cotswold Trust [A2437]
- Royal Marsden Cancer Charity
- Melanoma Research Alliance
- Cancer Research UK [C69256/A30194, C50947/A18176]
- National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital
- Institute of Cancer Research [A109]
- Kidney and Melanoma Cancer Fund of Royal Marsden Cancer Charity
- Ventana Medical Systems [10467, 10530]
- National Institute of Health (Bethesda)
- Damon Runyon Cancer Research Foundation [CI-98-18]
- Memorial Sloan Kettering Cancer Center [P30 CA008748]
- Stand Up to Cancer (SU2C)-American Cancer Society Lung Cancer Dream Team Translational research grant [SU2C-AACR-DT17-15]
- Post-Genome Technology Development Program - Ministry of Trade, Industry and Energy (MOTIE, Korea) [10067758]
- National Research Foundation of Korea (NRF) - Korea government (MSIT) [2020R1A2C3006535]
- Francis Crick Institute from Cancer Research UK [FC001202, FC001169]
- Wellcome Trust [FC001202, FC001169, 211179/Z/18/Z, FC10988]
- European Research Council [StG 677268 NextDART]
- National Institute for Health Research Biomedical Research Centre
- Idea to Innovation (i2i) Crick translation scheme - Medical Research Council
- Jean Shanks Foundation
- University College London
- Royal Society [211179/Z/18/Z]
- Cancer Research UK Lung Cancer Centre of Excellence
- Rosetrees
- NIHR BRC at University College London Hospitals
- Cancer Research UK-University College London (CRUK-UCL) Centre Award [C416/A25145]
- BloodCancer Research UK
- Cancer Research UK
- Rosetrees Trust
- Butterfield Trust
- Stoneygate Trust
- Novo Nordisk Foundation [ID16584]
- Royal Society Research Professorship Enhancement Award [RP/EA/180007]
- National Institute for Health Research (NIHR) Biomedical Research Centre at University College London Hospitals
- CRUK-UCL Centre
- Experimental Cancer Medicine Centre
- Breast Cancer Research Foundation (BCRF)
- SU2C-LUNGevity-American Lung Association Lung Cancer Interception Dream Team translational research grant [SU2C-AACR-DT23-17]
- European Research Council (ERC) under the European Union's Seventh Framework Programme (FP7/2007-2013) consolidator grant [FP7-THESEUS-617844]
- European Commission ITN [FP7-PloidyNet 607722]
- ERC advanced grant (PROTEUS) under the European Union's Horizon 2020 research and innovation program [835297]
- Chromavision from the European Union's Horizon 2020 research and innovation program [665233]
- CRUK Senior Cancer Research Fellowship [C36463/A22246]
- CRUK Biotherapeutic Program Grant [C36463/A20764]
- Stoneygate trust [A1388]
- Cancer Immunotherapy Accelerator Award (CITACRUK) [C33499/A20265]
- National Research Foundation of Korea [2020R1A2C3006535] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- MRC [MC_PC_17179, MR/M009033/1, MR/P014712/1] Funding Source: UKRI
Checkpoint inhibitors (CPIs) enhance adaptive immunity, with clonal tumor mutation burden (TMB) identified as the strongest predictor of CPI response. Dinucleotide variants may serve as a source of immunogenic epitopes, while copy-number alterations and HLA evolutionary divergence lack pan-cancer significance.
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.
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