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Sex-based dimorphism of anticancer immune response and molecular mechanisms of immune evasion
PURPOSE: We previously demonstrated that sex influences response to immune-checkpoint inhibitors. Here we investigate sex-based differences in the molecular mechanisms of anticancer immune-response and immune evasion in patients with NSCLC. EXPERIMENTAL DESIGN: We analyzed a) transcriptome-data of 2...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611463/ https://www.ncbi.nlm.nih.gov/pubmed/34016641 http://dx.doi.org/10.1158/1078-0432.CCR-21-0136 |
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author | Conforti, Fabio Pala, Laura Pagan, Eleonora Bagnardi, Vincenzo De Pas, Tommaso Queirolo, Paola Pennacchioli, Elisabetta Catania, Chiara Cocorocchio, Emilia Ferrucci, Pier Francesco Saponara, Maristella Orsolini, Gianmarco Zagami, Paola Nicoló, Eleonora De Marinis, Filippo Tortora, Giampaolo Bria, Emilio Minucci, Saverio Joffe, Hadine Veronesi, Paolo Wargo, Jennifer Rosenthal, Rachel Swanton, Charles Mantovani, Alberto Gelber, Richard D. Viale, Giuseppe Goldhirsch, Aron Giaccone, Giuseppe |
author_facet | Conforti, Fabio Pala, Laura Pagan, Eleonora Bagnardi, Vincenzo De Pas, Tommaso Queirolo, Paola Pennacchioli, Elisabetta Catania, Chiara Cocorocchio, Emilia Ferrucci, Pier Francesco Saponara, Maristella Orsolini, Gianmarco Zagami, Paola Nicoló, Eleonora De Marinis, Filippo Tortora, Giampaolo Bria, Emilio Minucci, Saverio Joffe, Hadine Veronesi, Paolo Wargo, Jennifer Rosenthal, Rachel Swanton, Charles Mantovani, Alberto Gelber, Richard D. Viale, Giuseppe Goldhirsch, Aron Giaccone, Giuseppe |
author_sort | Conforti, Fabio |
collection | PubMed |
description | PURPOSE: We previously demonstrated that sex influences response to immune-checkpoint inhibitors. Here we investigate sex-based differences in the molecular mechanisms of anticancer immune-response and immune evasion in patients with NSCLC. EXPERIMENTAL DESIGN: We analyzed a) transcriptome-data of 2575 early-stage NSCLCs from 7 different datasets; b) 327 tumor-samples extensively characterized at the molecular level from the TRACERx lung study; c) two independent cohorts of respectively 329 and 391 patients with advanced NSCLC treated with anti-PD1/anti-PDL1 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. By contrast, the TME of males was significantly enriched for a T-cells 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-PD1/PDL1 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. |
format | Online Article Text |
id | pubmed-7611463 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-76114632021-08-04 Sex-based dimorphism of anticancer immune response and molecular mechanisms of immune evasion Conforti, Fabio Pala, Laura Pagan, Eleonora Bagnardi, Vincenzo De Pas, Tommaso Queirolo, Paola Pennacchioli, Elisabetta Catania, Chiara Cocorocchio, Emilia Ferrucci, Pier Francesco Saponara, Maristella Orsolini, Gianmarco Zagami, Paola Nicoló, Eleonora De Marinis, Filippo Tortora, Giampaolo Bria, Emilio Minucci, Saverio Joffe, Hadine Veronesi, Paolo Wargo, Jennifer Rosenthal, Rachel Swanton, Charles Mantovani, Alberto Gelber, Richard D. Viale, Giuseppe Goldhirsch, Aron Giaccone, Giuseppe Clin Cancer Res Article PURPOSE: We previously demonstrated that sex influences response to immune-checkpoint inhibitors. Here we investigate sex-based differences in the molecular mechanisms of anticancer immune-response and immune evasion in patients with NSCLC. EXPERIMENTAL DESIGN: We analyzed a) transcriptome-data of 2575 early-stage NSCLCs from 7 different datasets; b) 327 tumor-samples extensively characterized at the molecular level from the TRACERx lung study; c) two independent cohorts of respectively 329 and 391 patients with advanced NSCLC treated with anti-PD1/anti-PDL1 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. By contrast, the TME of males was significantly enriched for a T-cells 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-PD1/PDL1 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. 2021-08-01 2021-05-20 /pmc/articles/PMC7611463/ /pubmed/34016641 http://dx.doi.org/10.1158/1078-0432.CCR-21-0136 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) International license. |
spellingShingle | Article Conforti, Fabio Pala, Laura Pagan, Eleonora Bagnardi, Vincenzo De Pas, Tommaso Queirolo, Paola Pennacchioli, Elisabetta Catania, Chiara Cocorocchio, Emilia Ferrucci, Pier Francesco Saponara, Maristella Orsolini, Gianmarco Zagami, Paola Nicoló, Eleonora De Marinis, Filippo Tortora, Giampaolo Bria, Emilio Minucci, Saverio Joffe, Hadine Veronesi, Paolo Wargo, Jennifer Rosenthal, Rachel Swanton, Charles Mantovani, Alberto Gelber, Richard D. Viale, Giuseppe Goldhirsch, Aron Giaccone, Giuseppe Sex-based dimorphism of anticancer immune response and molecular mechanisms of immune evasion |
title | Sex-based dimorphism of anticancer immune response and molecular mechanisms of immune evasion |
title_full | Sex-based dimorphism of anticancer immune response and molecular mechanisms of immune evasion |
title_fullStr | Sex-based dimorphism of anticancer immune response and molecular mechanisms of immune evasion |
title_full_unstemmed | Sex-based dimorphism of anticancer immune response and molecular mechanisms of immune evasion |
title_short | Sex-based dimorphism of anticancer immune response and molecular mechanisms of immune evasion |
title_sort | sex-based dimorphism of anticancer immune response and molecular mechanisms of immune evasion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611463/ https://www.ncbi.nlm.nih.gov/pubmed/34016641 http://dx.doi.org/10.1158/1078-0432.CCR-21-0136 |
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