Conforti, F; Pala, L; Pagan, E; Bagnardi, V; De Pas, T; Queirolo, P; Pennacchioli, E; ... Giaccone, G; + view all Conforti, F; Pala, L; Pagan, E; Bagnardi, V; De Pas, T; Queirolo, P; Pennacchioli, E; Catania, C; Cocorocchio, E; Ferrucci, PF; Saponara, M; Orsolini, G; Zagami, P; Nicoló, E; De Marinis, F; Tortora, G; Bria, E; Minucci, S; Joffe, H; Veronesi, P; Wargo, J; Rosenthal, R; Swanton, C; Mantovani, A; Gelber, RD; Viale, G; Goldhirsch, A; Giaccone, G; - view fewer (2021) Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion. Clinical Cancer Research , 27 (15) pp. 4311-4324. 10.1158/1078-0432.CCR-21-0136.

Preview

Text Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion.pdf - Accepted Version Download (2MB) | Preview

Abstract

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. TRANSLATIONAL RELEVANCE: It is well known that sex (i.e., the biological differences between men and women) and gender (i.e., behavioral differences associated with being male or female) are variables that affect immune responses to both foreign and selfantigens. Such sex- and gender-based dimorphism of immune system function, in turn reflects complex interactions between genes, hormones, the environment, and commensal microbiome composition. In our previous works, we showed that patients' sex is significantly associated with effectiveness of immune checkpoint inhibitors (ICIs) in patients with several solid tumors, including NSCLC. Here, we identified meaningful differences in molecular mechanisms that drive anticancer immune response as well as in immune evasion mechanisms exploited by NSCLCs arising in men and women. Importantly, we showed that all the findings reported, were not related to other variables potentially associated with sex such as patients' age, stage of disease, tumor histotype, and smoking status. The findings reported in this our work explain our previous clinical observations and can open this area to different immunotherapy strategies in males and females with NSCLC to further improve prognosis of both.

Download activity - last month

Export as XMLCSVJSON

Download activity - last 12 months

Export as JSONCSVXML

Downloads by country - last 12 months

Export as JSONCSVXML

Archive Staff Only

View Item