Assessing the mechanisms underlying the association between sex and immunotherapy response

Recently, immune checkpoint inhibitors have become a mainstay in the treatment of advanced non-small cell lung cancer (NSCLC) after demonstrating unprecedented clinical activity in several large clinical trials. However, data from a systematic analysis of these trials suggest that females may have less response to immune checkpoint inhibitors than experienced by males. If validated, this finding will highlight the need to explore new immunotherapy regimens specific for women. Furthermore, understanding differences in immunotherapy efficacy amongst females vs. males may also reveal important underlying mechanisms of therapeutic immunity and potentially even provide targets for future synergistic immunotherapy combinations. This proposal intends to use advanced statistical modeling and cutting-edge laboratory techniques to 1) determine if female sex is independently associated with decreased immunotherapy efficacy in patients with advanced lung cancer, 2) determine if differences in the pre-treatment composition of the tumor immune microenvironment (TIME) is responsible for the association of sex and immunotherapy, and 3) study the role of hormones such as estrogen as a mediator in the relationship between sex and immunotherapy response. Elucidating these potential important mediators of immunotherapy response will have significant implications in guiding the treatment and future study of immunotherapy in lung cancer.