Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 596-614.e14 |
| Journal | Cell |
| Volume | 184 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 4 2021 |
| Externally published | Yes |
Keywords
- biomarkers
- checkpoint inhibitors
- clonal TMB
- CXCL9
- immunogenicity
- immunotherapy
- meta-analysis
- mutation
- neoantigen
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
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In: Cell, Vol. 184, No. 3, 04.02.2021, p. 596-614.e14.
Research output: Contribution to journal › Article › peer-review
}
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 - Funding Information: We greatly thank all investigators, funders, and industry partners that supported the generation of the data within this study, as well as patients for their participation. Specifically, we thank Merck & Co, Genentech, and Bristol-Myers Squibb for generating the industry datasets used in this study, and Eli Van Allen, Luis Diaz, Timothy A Chan, Levi A Garraway, Roger S Lo, Dean F. Bajorin, Dirk Schadendorf, Thomas Powles, and Antoni Ribas for academic datasets. K.L. is funded by the UK Medical Research Council ( MR/P014712/1 ), the Rosetrees Trust and Cotswold Trust ( A2437 ), the Royal Marsden Cancer Charity (thanks to the Ross-Russell and Macfarlanes donations), Melanoma Research Alliance, and Cancer Research UK ( C69256/A30194 ). K.T. is funded by the Rosetrees Trust and Cotswold Trust ( A2437 ). S.T. is a Cancer Research UK clinician scientist and is funded by Cancer Research UK (grant C50947/A18176 ), the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital, the Institute of Cancer Research (grant A109 ), the Kidney and Melanoma Cancer Fund of Royal Marsden Cancer Charity (thanks to the Ross-Russell and Macfarlanes donations), the Rosetrees Trust (grant reference number A2204), Ventana Medical Systems (grant reference numbers 10467 and 10530), the National Institute of Health (Bethesda), and Melanoma Research Alliance. M.D.H. and this research are supported in part by the Damon Runyon Cancer Research Foundation (grant CI-98-18 ), the Memorial Sloan Kettering Cancer Center (support grant/core grant P30 CA008748 , and a Stand Up to Cancer (SU2C)-American Cancer Society Lung Cancer Dream Team Translational research grant (SU2C-AACR-DT17-15). SU2C is a program of the Entertainment Industry Foundation . Research grants are administered by the American Association for Cancer Research , the scientific partner of SU2C. M.D.H. is a member of the Parker Institute for Cancer Immunotherapy . This work was supported by the Post-Genome Technology Development Program (business model development driven by the clinico-genomic database for precision immuno-oncology) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea; grant 10067758 ). This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1A2C3006535 ). P.V.L. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK ( FC001202 ), the UK Medical Research Council ( FC001202 ), and the Wellcome Trust ( FC001202 ). P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support towards the establishment of The Francis Crick Institute. S.R.H is funded by the European Research Council (StG 677268 NextDART). D.B. is funded by the National Institute for Health Research Biomedical Research Centre and the Idea to Innovation (i2i) Crick translation scheme supported by the Medical Research Council, and was previously funded by the Jean Shanks Foundation and University College London. J.L. is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital, the Institute of Cancer Research (grant A109), and Royal Marsden Cancer Charity. N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant Number 211179/Z/18/Z ), and also receives funding from Cancer Research UK Lung Cancer Centre of Excellence, Rosetrees, and the NIHR BRC at University College London Hospitals. L.C. and J.A.G.-A. were funded by the Cancer Research UK-University College London (CRUK-UCL) Centre Award [C416/A25145]. T.E. and V.T. are supported by BloodCancer Research UK. C.S. is Royal Society Napier Research Professor. His work is supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( FC001169 ), the UK Medical Research Council ( FC001169 ), and the Wellcome Trust ( FC001169 ). C.S. is funded by Cancer Research UK (TRACERx, PEACE, and CRUK Cancer Immunotherapy Catalyst Network), the Cancer Research UK Lung Cancer Centre of Excellence , the Rosetrees Trust , the Butterfield and Stoneygate Trusts , the Novo Nordisk Foundation ( ID16584 ), a Royal Society Research Professorship Enhancement Award ( RP/EA/180007 ), the National Institute for Health Research (NIHR) Biomedical Research Centre at University College London Hospitals , the CRUK-UCL Centre , Experimental Cancer Medicine Centre , and the Breast Cancer Research Foundation (BCRF). This research is supported by a SU2C - LUNGevity - American Lung Association Lung Cancer Interception Dream Team translational research grant (SU2C-AACR-DT23-17). Research grants are administered by the American Association for Cancer Research , the Scientific Partner of SU2C. C.S. also receives funding from the 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 ), an ERC advanced grant (PROTEUS) under the European Union’s Horizon 2020 research and innovation program ( 835297 ), and Chromavision from the European Union’s Horizon 2020 research and innovation program ( 665233 ). S.A.Q. received a CRUK Senior Cancer Research Fellowship ( C36463/A22246 ) and is funded by a CRUK Biotherapeutic Program Grant ( C36463/A20764 ), the Rosetrees and Stoneygate trusts ( A1388 ), and a donation from the Khoo Teck Puat UK Foundation via the UCL Cancer Institute Research Trust ( 539288 ) and is supported by the Cancer Immunotherapy Accelerator Award (CITA-CRUK) ( C33499/A20265 ). The results published here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga . Grahical abstract created with biorender.com. This research was funded in whole, or in part, by the Wellcome Trust [FC001169, FC001202, FC10988]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Funding Information: We greatly thank all investigators, funders, and industry partners that supported the generation of the data within this study, as well as patients for their participation. Specifically, we thank Merck & Co, Genentech, and Bristol-Myers Squibb for generating the industry datasets used in this study, and Eli Van Allen, Luis Diaz, Timothy A Chan, Levi A Garraway, Roger S Lo, Dean F. Bajorin, Dirk Schadendorf, Thomas Powles, and Antoni Ribas for academic datasets. K.L. is funded by the UK Medical Research Council (MR/P014712/1), the Rosetrees Trust and Cotswold Trust (A2437), the Royal Marsden Cancer Charity (thanks to the Ross-Russell and Macfarlanes donations), Melanoma Research Alliance, and Cancer Research UK (C69256/A30194). K.T. is funded by the Rosetrees Trust and Cotswold Trust (A2437). S.T. is a Cancer Research UK clinician scientist and is funded by Cancer Research UK (grant C50947/A18176), the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital, the Institute of Cancer Research (grant A109), the Kidney and Melanoma Cancer Fund of Royal Marsden Cancer Charity (thanks to the Ross-Russell and Macfarlanes donations), the Rosetrees Trust (grant reference number A2204), Ventana Medical Systems (grant reference numbers 10467 and 10530), the National Institute of Health (Bethesda), and Melanoma Research Alliance. M.D.H. and this research are supported in part by the Damon Runyon Cancer Research Foundation (grant CI-98-18), the Memorial Sloan Kettering Cancer Center (support grant/core grant P30 CA008748, and a Stand Up to Cancer (SU2C)-American Cancer Society Lung Cancer Dream Team Translational research grant (SU2C-AACR-DT17-15). SU2C is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. M.D.H. is a member of the Parker Institute for Cancer Immunotherapy. This work was supported by the Post-Genome Technology Development Program (business model development driven by the clinico-genomic database for precision immuno-oncology) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea; grant 10067758). This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1A2C3006535). P.V.L. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202). P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support towards the establishment of The Francis Crick Institute. S.R.H is funded by the European Research Council (StG 677268 NextDART). D.B. is funded by the National Institute for Health Research Biomedical Research Centre and the Idea to Innovation (i2i) Crick translation scheme supported by the Medical Research Council, and was previously funded by the Jean Shanks Foundation and University College London. J.L. is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital, the Institute of Cancer Research (grant A109), and Royal Marsden Cancer Charity. N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant Number 211179/Z/18/Z), and also receives funding from Cancer Research UK Lung Cancer Centre of Excellence, Rosetrees, and the NIHR BRC at University College London Hospitals. L.C. and J.A.G.-A. were funded by the Cancer Research UK-University College London (CRUK-UCL) Centre Award [C416/A25145]. T.E. and V.T. are supported by BloodCancer Research UK. C.S. is Royal Society Napier Research Professor. His work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C.S. is funded by Cancer Research UK (TRACERx, PEACE, and CRUK Cancer Immunotherapy Catalyst Network), the Cancer Research UK Lung Cancer Centre of Excellence, the Rosetrees Trust, the Butterfield and Stoneygate Trusts, the Novo Nordisk Foundation (ID16584), a Royal Society Research Professorship Enhancement Award (RP/EA/180007), the National Institute for Health Research (NIHR) Biomedical Research Centre at University College London Hospitals, the CRUK-UCL Centre, Experimental Cancer Medicine Centre, and the Breast Cancer Research Foundation (BCRF). This research is supported by a SU2C-LUNGevity-American Lung Association Lung Cancer Interception Dream Team translational research grant (SU2C-AACR-DT23-17). Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. also receives funding from the 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), an ERC advanced grant (PROTEUS) under the European Union's Horizon 2020 research and innovation program (835297), and Chromavision from the European Union's Horizon 2020 research and innovation program (665233). S.A.Q. received a CRUK Senior Cancer Research Fellowship (C36463/A22246) and is funded by a CRUK Biotherapeutic Program Grant (C36463/A20764), the Rosetrees and Stoneygate trusts (A1388), and a donation from the Khoo Teck Puat UK Foundation via the UCL Cancer Institute Research Trust (539288) and is supported by the Cancer Immunotherapy Accelerator Award (CITA-CRUK) (C33499/A20265). The results published here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. Grahical abstract created with biorender.com. This research was funded in whole, or in part, by the Wellcome Trust [FC001169, FC001202, FC10988]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. K.L. J.L.R. S.Q. N.M. and C.S. designed the study. J.L.R. V.T. and A.J.S.F. performed laboratory experiments. C.A. M.D.H. S.T. and J.L. performed clinical work. K.L. J.R. C.P. K.T. R.B. T.B.K.W. R.R. D.B. E.L. M.A.B. J.A.G.-A. and L.C. analyzed data. A.R. S.K.S. S.R.H. J.H. T.E. S.-H. L. and P.V.L. interpreted data. K.L. J.L.R. M.D.H. N.M. S.Q. and C.S. wrote the manuscript. K.L. has a patent on indel burden and CPI response pending and outside of the submitted work, speaker fees from Roche tissue diagnostics, research funding from CRUK TDL/Ono/LifeArc alliance, and a consulting role with Monopteros Therapeutics. S.T. has received speaking fees from Roche, AstraZeneca, Novartis, and Ipsen. S.T. has the following patents filed: Indel mutations as a therapeutic target and predictive biomarker PCTGB2018/051892 and PCTGB2018/051893 and Clear Cell Renal Cell Carcinoma Biomarkers P113326GB. S.Q. reports personal fees and employment with Achilles Therapeutics (where he is CSO) outside of the submitted work. J.L.R. consults for Achilles Therapeutics. N.M. has received consultancy fees and has stock options in Achilles Therapeutics. N.M. holds European patents relating to targeting neoantigens (PCT/EP2016/ 059401), identifying patient response to immune checkpoint blockade (PCT/ EP2016/071471), determining HLA LOH (PCT/GB2018/052004), and predicting survival rates of patients with cancer (PCT/GB2020/050221). C.A. receives research salary from AstraZeneca and is an AstraZeneca Fellow and acting study physician on the MERMAID-1 study. C.A. holds pending patents in methods to detect tumor recurrence (PCT/GB2017/053289). C.A. and C.S. declare patent PCT/US2017/028013 for methods to detect lung cancer. C.A. has received speaker fees from Novartis, Roche Diagnostics, Bristol Myers Squibb, and AstraZeneca and was an advisory board member for AstraZeneca. M.D.H. has stock and other ownership interests in Shattuck Labs, Immunai, and Arcus Biosciences; reports honoraria from AstraZeneca and Bristol-Myers Squibb; has a consulting or advisory role with Bristol-Myers Squibb, Merck, Genentech/Roche, AstraZeneca, Nektar, Syndax, Mirati Therapeutics, Shattuck Labs, Immunai, Blueprint Medicines, Achilles Therapeutics, and Arcus Biosciences; receives research funding from Bristol-Myers Squibb (Inst); has patents, royalties, and other intellectual property (a patent has been filed by Memorial Sloan Kettering [PCT/US2015/062208] for the use of TMB for prediction of immunotherapy efficacy, which is licensed to Personal Genome Diagnostics); and receives travel and accommodation expense reimbursement from AstraZeneca, Bristol-Myers Squibb, and Eli Lilly. J.L. reports personal fees from Eisai, GlaxoSmithKline, Kymab, Roche/Genentech, Secarna, Pierre Fabre, and EUSA Pharma and grants and personal fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and Novartis outside of the submitted work. C. Swanton acknowledges grant support from Pfizer, AstraZeneca, Bristol-Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx (collaboration in minimal residual disease sequencing technologies), and Ono Pharmaceutical; is an AstraZeneca advisory board member and chief investigator for the MeRmaiD1 clinical trial; has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol-Myers Squibb, Celgene, Amgen, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, Bicycle Therapeutics, and the Sarah Cannon Research Institute; has stock options in Apogen Biotechnologies, Epic Bioscience, and GRAIL; and has stock options and is co-founder of Achilles Therapeutics. C.S. holds European patents relating to assay technology to detect tumor recurrence (PCT/GB2017/053289), targeting neoantigens (PCT/EP2016/059401), identifying patient response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), and identifying patients who respond to cancer treatment (PCT/GB2018/051912), as well as a US patent relating to detecting tumor mutations (PCT/US2017/28013) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). S.R.H. is co-founder of Tetramershop and PokeAcell. D.B. reports personal fees from NanoString, outside this work, and he has a patent PCT/GB2020/050221 issued on methods for cancer prognostication. Funding Information: K.L. has a patent on indel burden and CPI response pending and outside of the submitted work, speaker fees from Roche tissue diagnostics, research funding from CRUK TDL/Ono/LifeArc alliance, and a consulting role with Monopteros Therapeutics. S.T. has received speaking fees from Roche, AstraZeneca, Novartis, and Ipsen. S.T. has the following patents filed: Indel mutations as a therapeutic target and predictive biomarker PCTGB2018/051892 and PCTGB2018/051893 and Clear Cell Renal Cell Carcinoma Biomarkers P113326GB. S.Q. reports personal fees and employment with Achilles Therapeutics (where he is CSO) outside of the submitted work. J.L.R. consults for Achilles Therapeutics. N.M. has received consultancy fees and has stock options in Achilles Therapeutics. N.M. holds European patents relating to targeting neoantigens (PCT/EP2016/ 059401), identifying patient response to immune checkpoint blockade (PCT/ EP2016/071471), determining HLA LOH (PCT/GB2018/052004), and predicting survival rates of patients with cancer (PCT/GB2020/050221). C.A. receives research salary from AstraZeneca and is an AstraZeneca Fellow and acting study physician on the MERMAID-1 study. C.A. holds pending patents in methods to detect tumor recurrence (PCT/GB2017/053289). C.A. and C.S. declare patent PCT/US2017/028013 for methods to detect lung cancer. C.A. has received speaker fees from Novartis, Roche Diagnostics, Bristol Myers Squibb, and AstraZeneca and was an advisory board member for AstraZeneca. M.D.H. has stock and other ownership interests in Shattuck Labs, Immunai, and Arcus Biosciences; reports honoraria from AstraZeneca and Bristol-Myers Squibb; has a consulting or advisory role with Bristol-Myers Squibb, Merck, Genentech/Roche, AstraZeneca, Nektar, Syndax, Mirati Therapeutics, Shattuck Labs, Immunai, Blueprint Medicines, Achilles Therapeutics, and Arcus Biosciences; receives research funding from Bristol-Myers Squibb (Inst); has patents, royalties, and other intellectual property (a patent has been filed by Memorial Sloan Kettering [PCT/US2015/062208] for the use of TMB for prediction of immunotherapy efficacy, which is licensed to Personal Genome Diagnostics); and receives travel and accommodation expense reimbursement from AstraZeneca, Bristol-Myers Squibb, and Eli Lilly. J.L. reports personal fees from Eisai, GlaxoSmithKline, Kymab, Roche/Genentech, Secarna, Pierre Fabre, and EUSA Pharma and grants and personal fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and Novartis outside of the submitted work. C. Swanton acknowledges grant support from Pfizer, AstraZeneca, Bristol-Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx (collaboration in minimal residual disease sequencing technologies), and Ono Pharmaceutical; is an AstraZeneca advisory board member and chief investigator for the MeRmaiD1 clinical trial; has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol-Myers Squibb, Celgene, Amgen, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, Bicycle Therapeutics, and the Sarah Cannon Research Institute; has stock options in Apogen Biotechnologies, Epic Bioscience, and GRAIL; and has stock options and is co-founder of Achilles Therapeutics. C.S. holds European patents relating to assay technology to detect tumor recurrence (PCT/GB2017/053289), targeting neoantigens (PCT/EP2016/059401), identifying patient response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), and identifying patients who respond to cancer treatment (PCT/GB2018/051912), as well as a US patent relating to detecting tumor mutations (PCT/US2017/28013) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). S.R.H. is co-founder of Tetramershop and PokeAcell. D.B. reports personal fees from NanoString, outside this work, and he has a patent PCT/GB2020/050221 issued on methods for cancer prognostication. Publisher Copyright: © 2021 Elsevier Inc.
PY - 2021/2/4
Y1 - 2021/2/4
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.
KW - biomarkers
KW - checkpoint inhibitors
KW - clonal TMB
KW - CXCL9
KW - immunogenicity
KW - immunotherapy
KW - meta-analysis
KW - mutation
KW - neoantigen
UR - http://www.scopus.com/inward/record.url?scp=85100246027&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100246027&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2021.01.002
DO - 10.1016/j.cell.2021.01.002
M3 - Article
C2 - 33508232
AN - SCOPUS:85100246027
SN - 0092-8674
VL - 184
SP - 596-614.e14
JO - Cell
JF - Cell
IS - 3
ER -