Advisor(s)
Lalita Shevde-Samant
Committee Member(s)
Gregory Payne
Jianmei Leavenworth
Robert Welner
Selvarangan Ponnazhagan
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Pathology
Date of Award
9-11-2025
Abstract
Breast cancer impacts 1 in 8 women in the United States. The mammary tumor microenvironment (TME) holds both immunostimulatory and immunosuppressive constituents that modulate tumor progression, eradication, and treatment response. Triple-negative breast cancer (TNBC) has an immunologically ‘cold’ TME due to the infiltration of immunosuppressive regulatory T cells (Tregs) and the presence of dysfunctional CD8+ T cells. As these are two key populations involved in immune escape, it is vital to discover novel mechanisms of Treg immunosuppression and CD8+ T cell exhaustion in TNBC. This work identifies the mechanistic role of Hedgehog (Hh) signaling, a tumor-promotive pathway, in stimulating Treg suppression and accelerating CD8+ T cell exhaustion in breast cancer. Studies utilizing a novel genetically engineered mouse model revealed the role of Gli2 signaling in Treg plasticity and suppression. Additionally, systemic Hh inhibition in syngeneic mouse models of TNBC modified the TME to be more supportive of effector differentiation and the proliferative fitness of CD8+ T cells. Direct Hh inhibition resulted in the augmented accumulation of TCF1+ stem-like progenitor CD8+ T cells (Tpex) and their differentiation into cytotoxic TCF1- terminally exhausted effector CD8+ T cells (Tex), a critical transition during CD8+ T cell exhaustion that is habitually dysfunctional during tumorigenesis. In-depth transcriptomic studies revealed that Hh inhibition reprogrammed and reinforced CD8+ T cells to maintain a proliferative Tpex profile after initial stimulation, and upon re-stimulation, effectively differentiate into Tex cells. And lastly, comorbidities trivialize treatment and prognoses for breast cancer patients, and therefore, understanding how the highly prevalent chronic condition, type 2 diabetes (T2D), can impact tumorigenesis and transform the tumor-immune milieu is critical. Hyperglycemia can also induce Hh activity. Studies were conducted to query the tumor immune landscape in a preclinical model of diabetes-associated hyperglycemia. Comprehensive assessments profiling T lymphocytes, as well as myeloid populations and immune-relevant transcriptomic signatures, in a T2D-TNBC mouse model revealed the intensified immunosuppressed TME in the primary tumor and premetastatic niche of the lungs. Collectively and contextually, this work supports the initiative to: (i) target Hh signaling, or (ii) mitigate aberrantly activated signaling in conditions of hyperglycemia to relieve the immunosuppressive pressure within the TME, thereby improving therapy response and clinical outcomes for patients with highly aggressive TNBC.
ProQuest ID
Recommended Citation
Swain, Courtney Anitra, "Mechanisms Impacting Regulatory T Cell Activity And Cd8+ T Cell Exhaustion In Breast Cancer" (2025). All ETDs from UAB. 7400.
https://digitalcommons.library.uab.edu/etd-collection/7400
