Abstract A090: Investigating the role of androgen signaling in the PDAC tumor microenvironment

Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival rate of 12.5%. Like many non-reproductive cancers, sex dimorphisms are observed in the incidence and mortality rates of PDAC. Males carry a higher incidence rate (15.4) compared to females (12), with mortality rates following the same trend. While sex-specific environmental influences may be at play, sex-specific biological factors such as sex chromosomes and sex hormones have been attributed to disparities in various disease contexts including autoimmunity, neurological function, and metabolic disorders. Previous reports describe the treatment of male PDAC patients with the anti-androgen drug flutamide, which resulted in enhanced survival and suggests a pro-tumor role for androgen signaling in PDAC. Androgens are known to suppress myeloid and T cell responses, resulting in higher incidence of autoimmunity in females. Androgens are also implicated in dermal fibroblast proliferation, migration, and collagen-production. Therefore, we hypothesized that androgen receptor (AR) signaling in immune cells and pancreatic stellate cells (PSCs) leads to immunosuppression and development of pro-tumor PSCs in the PDAC tumor microenvironment (TME). To investigate this hypothesis, castration (GDX) and sham GDX operations were performed on male mice 1-2 weeks prior to tumor implantation. KPCY 6419 (Kerafast) tumor cells were injected into the pancreata of B6 and TCRbd KO mice. Tumors were harvested after 22-24 days and tumor-infiltrating lymphocytes (TILs) were isolated and analyzed with flow cytometry. Sham male mice had larger tumors and impaired T cell responses compared to females and GDX males. Indeed, flow cytometric analysis revealed less T cell infiltration, less progenitor-exhausted CD8+ T cells (CD8+PD-1+TCF-1+), and less cytotoxic T cells (CD8+TNFa+, CD8+GZMB+) in sham male tumors. Tumor burden did not differ between male TCRbd KO sham vs. GDX mice, indicating that AR signaling may not be dependent on T cells. Tumor sections were stained with alpha smooth muscle actin (SMA) and Masson’s Trichrome technique, which revealed PSC activation in GDX males but minimal changes in collagen deposition. Primary PSCs were isolated from human and murine tissue and SMA and AR expression was validated. The effects of 100 nM dihydrotestosterone (DHT) treatment on PSC gene expression was analyzed, revealing expansive changes in metabolic and extracellular matrix (ECM)-forming pathways. Preliminary data suggests that secreted factors from AR-treated PSCs may play a role in promoting tumor cell growth, while enhanced desmoplasia may promote immune exclusion. These data reveal the role of AR signaling in modulating the PDAC TME, ultimately leading to a pro-tumor environment that does not support effective anti-tumor T cell responses. These results are important in understanding the male bias in PDAC incidence and mortality and serve as the groundwork for a novel potential therapeutic target. Citation Format: Quinn Hopen, Michael Sestito, MD, Benjamin Duncan, Britney Niemann, MD, Tyler Augenstein, Jonathan Busada, PhD, Jennifer Franko, PhD, Brian Boone, MD. Investigating the role of androgen signaling in the PDAC tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A090.