Author ORCID Identifier

https://orcid.org/0000-0003-2911-8216

Semester

Summer

Date of Graduation

2026

Document Type

Dissertation (Campus Access)

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Brian A. Boone

Committee Member

Jennifer Franko

Committee Member

Tracy W. Liu

Committee Member

Jonathan T. Busada

Committee Member

Timothy D. Eubank

Committee Member

Scott Weed

Abstract

Sex differences in cancer risk are well described and have significant implications for the application of precision medicine. Sex-specific immune activation is well documented, which raises the possibility that sex-specific anti-tumor immunity may regulate growth and progression of solid tumors. The work herein investigates the influence of sex hormones on the immune microenvironment of head and neck squamous cell carcinoma (HNSCC) and pancreatic ductal adenocarcinoma (PDAC) tumors. Further, we explore the disparate regulation of sex-specific tumor growth between immune-rich HNSCC tumors and immune-excluded PDAC tumors. In HNSCC, mice in both the carcinogen-induced 4-nitroquinolone-1-oxide (4-NQO) model and the murine oral squamous cell carcinoma (MOC1) orthotopic model exhibited male-biased disease progression. Similarly, male biases were noted in spontaneous, orthotopic, and liver metastasis models of PDAC. Moreover, castrated male mice demonstrated reduced HNSCC and PDAC orthotopic tumor burden compared to sham-operated males, revealing the androgen-mediated nature of male-biased tumor growth. Female mice possessed enhanced anti-tumor T cell infiltration compared to males, and castration enhanced male T cell responses, suggesting the role of androgens in anti-tumor T cell suppression. In the orthotopic HNSCC model, sex-specific tumor burden was abrogated in T cell receptor knockout (TCR KO) male and female mice bearing MOC1 tumors, suggesting that androgens drive HNSCC growth in a T cell dependent manner. In contrast, androgen-driven PDAC growth was demonstrated to be T cell independent. Instead, androgen receptor (AR) signaling in PDAC-associated fibroblasts (CAFs) reprogrammed CAFs to support KPCY intracellular lipid storage and proliferation. These findings suggest that in tumors with sufficient immune infiltration, androgens drive tumor growth and progression by suppressing anti-tumor T cells. However, in highly immune-excluded tumors, T cell suppression is insufficient to drive androgen-mediated tumor growth, and thus, androgens promote tumor growth through modulation of the stroma. Collectively, the work presented here demonstrates the role of the tumor immune microenvironment in shaping divergent mechanisms of androgen-mediated tumor growth. Further, this dissertation highlights the potential utility of therapeutically targeting androgens to restrict disease progression by enhancing anti-tumor immunity and inhibiting tumor-promoting functions of CAFs in solid tumor patients.

Download

Share

COinS