227P Sexual dimorphism in immune profile of early and advanced NSCLC

We determined whether sex-associated tissue and blood immune background characterizes surgically resected NSCLC and advanced patients undergoing immunotherapy (IO), potentially affecting clinical outcome. Peripheral blood, collected at surgery from stage I-III, and at baseline and first disease assessment (T1) from (chemo)-IO treated NSCLC, was subjected to FACS analysis of multiple cellular immunophenotypic and functional properties and to multiplex ELISA assay to measure serum cytokines. Tumor Immune Microenvironment (TIME) was assessed by IHC on surgical samples. These parameters were statistically correlated with clinical characteristics. Surgical cohort (n=123; 65 male M, 58 female F): blood immune profile of males was characterized by higher effector (CD8+GnzB+, CD8+PD1+ and CD3-CD56+CD16+ NK) cells and CD14+ monocytes (P < 0.05), while CD4+ and B lymphocytes (P < 0.05) prevailed in females, also exhibiting higher TGFβ1 serum level. Intriguingly, a parallel background was observed at tumor site where increased PD1+ cells (P = 0.04) featured male TIME, whereas CD4 density was higher in women (P = 0.03), also disclosing higher % of PD-L1low cases. Survival outcome appeared to favor female patients. Metastatic cohort (n=153; 103 M, 50 F): significantly higher CD4 number and proliferation and B cells persisted in baseline F blood from advanced cases (P < 0.05). Similarly, a clear trend towards increased cycling or PD1+CD8 and NKs (P = 0.05) was confirmed in M. The CD4- and B-driven immune response in F and the dominant cytotoxic CD8 (P < 0.04) and NK (P = 0.07) effector phenotypes in M were maintained at T1. Moreover, while CD4+CD25+FOXP3high Tregs rose in males following IO, this immunosuppressive counterbalance was eluded in females. A sex-dependent modulation of serum TGFβ1, sPD-L1, IL-6 and TNFα ultimately enclosed a divergent baseline and dynamic cellular/humoral profile underlying the increased incidence (67%) of irAEs in females (P = 0.03). Finally, a trend towards longer median OS and PFS was apparent in IO-treated female NSCLC. The immunity of early and advanced NSCLC patients is trained by gender and might contribute to the heterogeneity of tumor-host interaction and its clinical impact.