Abstract 670: Sex differences in the innate immune response to lung cancer

Abstract Lung cancer is the second most diagnosed cancer. Lung cancer exhibits a sex difference, though the exact mechanisms behind this difference are not well understood. Men have a higher lifetime risk of developing lung cancer and often have more severe disease than women. There are thought to be multiple factors that contribute to this difference, including the environment, lifestyle, sex hormones, and differing immune responses. Mouse tumor models of lung, breast, colon, melanoma and kidney were used in immune competent or immune compromised mouse models treated with the chemotherapy ABT-263. The study of the immune response to lung tumors utilized ex vivo killing assays, multicolor flow cytometry, and clonogenic survival, as well as humanized mice and patient-derived xenografts. We observe a sex difference in two models of lung cancer in immunocompetent mice, but not in models of breast, colon, kidney, or melanoma. This difference is dependent on the innate immune system, specifically through natural killer cells and macrophages. This sex difference is lost in ovariectomized mice. Multicolor flow cytometry shows differences in innate immune cell populations in tumors and spleens in males and females. Preliminary data suggests the pro-apoptotic ligand TRAIL secreted from innate immune cells is more effective on cells exposed to female compared to ovariectomized female mouse serum. Reduced tumor growth in female mice can be further enhanced with ABT-263, and this effect requires NK cells. Patient-derived xenografts transplanted into female humanized mice grow more slowly than those transplanted into non-humanized mice, confirming the role of the immune system in modulating tumor growth. This research opens the potential for immune stimulating therapies, combined with ABT-263, as a novel treatment approach. Citation Format: Lauren A. May, Joseph W. Landry, Rebecca Martin, Howard Y. Li, Jennifer Koblinski, Paula D. Bos. Sex differences in the innate immune response to lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 670.