TY - JOUR
T1 - Sex-based dimorphism of anticancer immune response and molecular mechanisms of immune evasion
AU - Conforti, Fabio
AU - Pala, Laura
AU - Pagan, Eleonora
AU - Bagnardi, Vincenzo
AU - De Pas, Tommaso
AU - Queirolo, Paola
AU - Pennacchioli, Elisabetta
AU - Catania, Chiara
AU - Cocorocchio, Emilia
AU - Ferrucci, Pier Francesco
AU - Saponara, Maristella
AU - Orsolini, Gianmarco
AU - Zagami, Paola
AU - Nicolo, Eleonora
AU - De Marinis, Filippo
AU - Tortora, Giampaolo
AU - Bria, Emilio
AU - Minucci, Saverio
AU - Joffe, Hadine
AU - Veronesi, Paolo
AU - Wargo, Jennifer
AU - Rosenthal, Rachel
AU - Swanton, Charles
AU - Mantovani, Alberto
AU - Gelber, Richard D.
AU - Viale, Giuseppe
AU - Goldhirsch, Aron
AU - Giaccone, Giuseppe
N1 - Funding Information:
P. Queirolo reports advisory board relationships at Roche, Novartis, MSD, BMS, Sun Pharma, Sanofi, and Pierre Fabre. P.F. Ferrucci reports grants, personal fees, and nonfinancial support from BMS, personal fees from Roche and Novartis, and personal fees and nonfinancial support from MSD and Pierre Fabre outside the submitted work. F. De Marinis reports other support from BMS, AstraZeneca, and ROCHE outside the submitted work. G. Tortora reports other support from BMS, MSD, and AstraZeneca outside the submitted work. E. Bria reports personal fees from MSD, AstraZeneca, Celgene, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis and Roche and grants from AstraZeneca and Roche outside the submitted work. H. Joffe reports grant support for a research program from NIH/Brigham & Women’s Hospital Funds, V Foundation, Merck, Pfizer, Que-Oncology, and NeRRe/KaNDy; consultant/ advisory roles with NeRRe/KaNDy, Merck, Sojournix, Eisai, Jazz Pharmaceutical; and spouse’s relationships with Merck Research Labs (employee), Arsenal Biosciences (consulting and equity), and Tango (equity). J.A. Wargo reports personal fees from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, Bristol Myers Squibb, Roche/Genentech, Novartis, AstraZeneca, Merck, Ella Therapeutics, and Micronoma outside the submitted work; and has a patent for PCT/US17/53.717 issued to MD Anderson and a patent for UTSC.P1412US.P1 – MDA19–023 issued to MD Anderson. R. Rosenthal reports personal fees from Achilles Therapeutics outside the submitted work and reports employment with Achilles Therapeutics. C. Swanton reports grants and personal fees from Pfizer, Bristol Myers Squibb, Ono Pharmaceuticals, Roche-Ventana, and AstraZeneca, grants from Boehringer-Ingelheim and Archer Dx Inc., personal fees from Novartis, MSD, Illumina, GlaxoSmithKline, Genentech, Medicxi, Sarah Canon Research Institute, and Bicycle Therapeutics, other support from Apogen Biotechnologies and Epic Biosciences, and personal fees and other support from GRAIL and Achilles Therapeutics during the conduct of the study; grants and personal fees from Pfizer, Bristol Myers Squibb, Ono Pharmaceuticals, Roche-Ventana, and AstraZeneca, grants from Boehringer-Ingelheim and Archer DX Inc., and personal fees from Novartis, MSD, Illumina, GlaxoSmithKline, Genentech,
Funding Information:
Medixci, Bicycle Therapeutics, Sarah Canon Research Institute GRAIL, Epic Biosciences, Apogen Biotechnologies, and Achilles Therapeutics outside the submitted work; and also has a patent for Immune checkpoint intervention in cancer (PCT/EP2016/071471) issued, a patent for Method for treating cancer based on identification of clonal neo-antigens (PCT/EP2016/059401) issued, a patent for Methods for lung cancer detection (PCT/US2017/028013) issued, a patent for Method of detecting tumour recurrence (PCT/GB2017/053289) issued, a patent for Method for treating cancer (PCT/EP2016/059401) issued, a patent for Method of treating cancer by targeting insertion/deletion mutations (PCT/GB2018/051893) issued, a patent for Method of identifying insertion/deletion mutation targets (PCT/GB2018/ 051892) issued, a patent for Method for determining whether an HLA allele is lost in a tumour (PCT/GB2018/052004) issued, a patent for Method for identifying responders to cancer treatment (PCT/GB2018/)051912) issued, and a patent for Method of predicting survival rates for cancer patients (PCT/GB2020/050221) issued; and is Royal Society Napier Research Professor. C.S. Swanson also reports that this work was supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). This research was funded in whole, or in part, by the Wellcome Trust (FC001169). 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. C.S. Swanson is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Centre of Excellence, the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society 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 Stand Up To Cancer–LUNGevity–American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant No. SU2C-AACR-DT23–17). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. Swanson 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) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 835297), and Chromavision from the European Union’s Horizon 2020 research and innovation programme (grant agreement 665233). A. Mantovani reports personal fees from Ventana, Pierre Fabre, Verily, AbbVie, AstraZeneca, Verseau Therapeutics, Compugen, Third Rock Venture, Imcheck Therapeutics, Ellipses, Novartis, Roche, Macrophage Pharma, BiovelocITA, Merck, and Principia, grants from Myeloid Therapeutics, and Novartis, and other support from Cedarlane Laboratories Ltd., HyCult Biotechnology, eBioscience, Biolegend, ABCAM Plc, Novus Biologicals, Enzo Life (ex Alexis Corp.), and Affy-metrix outside the submitted work; also has a patent for WO2019057780 “Antihuman migration stimulating factor (MSF) and uses thereof” pending and issued, a patent for WO2019081591 “NK or T cells and use thereof” pending and issued, a patent for WO2020127471 “Use of SAP for the treatment of Euromycetes fungi infections” pending and issued, and a patent for EP20182181.6 “PTX3 as a prognostic marker in COVID-19” pending. R.D. Gelber reports grants from Roche, AstraZeneca,
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - Purpose: We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC. Experimental Design: We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti–PD-1/anti–PD-L1 drugs. Results: As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell–excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti–PD-1/PD-L1 drugs. Conclusions: We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.
AB - Purpose: We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC. Experimental Design: We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti–PD-1/anti–PD-L1 drugs. Results: As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell–excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti–PD-1/PD-L1 drugs. Conclusions: We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.
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U2 - 10.1158/1078-0432.CCR-21-0136
DO - 10.1158/1078-0432.CCR-21-0136
M3 - Review article
C2 - 34016641
AN - SCOPUS:85111629129
SN - 1078-0432
VL - 27
SP - 4311
EP - 4324
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -