Abstract P045: γδ T cells contribute to an inflammatory and immunosuppressive microenvironment in lung squamous cell carcinoma tumorigenesis

Abstract Lung cancer (LC) is the leading cause of cancer death worldwide. Lung squamous cell carcinoma (LSCC) is the second most prevalent subtype of LC, accounting for approximately 22% of cases. It is strongly associated with smoking, with approximately 90% of cases attributable to cigarette smoke exposure. Despite the strong association with smoking, not all smokers will develop lung cancer. From this, two key questions arise: which patients will develop the lesions preceding LSCC, and among those, which will progress to frank carcinoma? Stratification of at-risk patients for diversion into intervention and prevention strategies, such as increased monitoring and chemical interception, remains an urgent need, and a greater understanding of the factors contributing to progression of LSCC premalignancy is critical in addressing this. Previous evidence suggests a role for the immune system in the development of preinvasive disease, and we hypothesize that immune differences between at-risk smokers may also play a role in which patients progress on to frank LSCC and which do not. Using the N-Nitrosotris-(2-chloroethyl) urea (NTCU) carcinogen-induced murine model of LSCC, we sought to explore the immune contexture of LSCC premalignancy in both NTCU-sensitive and NTCU-resistant mouse strains. We immunophenotyped mouse lungs via flow cytometry and imaging mass cytometry over the course of disease initiation and progression to carcinoma. We found that although the frequency of γδ T cells in control animals were the same between sensitive and resistant mice, in sensitive mice the frequency of γδ T cells and the expression of activation/exhaustion markers increased with histological progression of PMLs, along with a decrease in the frequency of cytotoxic CD8+ T cells. Given that pro-tumor γδ T cells have been established to mediate airway inflammation via recruitment of myeloid cells (e.g., macrophages, neutrophils, and myeloid derived suppressor cells) and to influence maturation/exhaustion of T cells, these findings suggest γδ T cells potentially contribute to the early establishment of an inflammatory and immunosuppressive microenvironment in developing LSCC premalignancy. By better understanding how immune alterations within the precancerous microenvironment contribute to lesion progression, immunomodulatory intervention agents can be developed and deployed in at-risk patients to ameliorate the development of frank lung squamous cell carcinoma and ultimately reduce LC mortality. Citation Format: Táchira Pichardo, Anna Belkina, Jennifer Snyder-Cappione, Jennifer Beane, Sarah Mazzilli. γδ T cells contribute to an inflammatory and immunosuppressive microenvironment in lung squamous cell carcinoma tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P045.