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; Nicolo, Eleonora; De Marinis, Filippo; Tortora, Giampaolo; Bria, Emilio; Minucci, Saverio; Joffe, Hadine; Veronesi, Paolo; Wargo, Jennifer A; Rosenthal, Rachel; Swanton, Charles; Mantovani, Alberto; Gelber, Richard D; Viale, Giuseppe; Goldhirsch, Aron; Giaccone, Giuseppe

PURPOSE We previously demonstrated that sex influences response tovimmune-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.