Author ORCID Identifier
https://orcid.org/0000-0002-7611-7729
Date of Award
2024
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
Mary Jo Turk
Abstract
Achieving durable, systemic CD8+ T cell responses against tumors is an imperative goal in treating cancer. However, suppressive cells, including Foxp3+CD4+ regulatory T cells (Tregs) are widely recognized to inhibit CD8+ T cell activity. For nearly two decades, anti-CD4 treatment has been used to eliminate Tregs and induces durable tumor antigen (Ag) specific CD8+ T cells, despite also depleting Foxp3-negative conventional CD4+ T (Tconv) cells. However, the underlying mechanism of anti-CD4 efficacy is not understood. In Chapter Three, we look beyond Treg depletion and investigate the potential contributions of other factors including homeostatic space, depletion of CD4+ APCs, and presence of suppressive Foxp3-negative CD4+ Tconv cells. Ultimately, we conclude that eliminating both Foxp3+ and Foxp3-negative CD4+ T cells is necessary to induce Ag specific CD8+ T cell priming, dissemination and persistence. Moreover, compared to anti-PD-1 and anti-CTLA-4 therapy, anti-CD4 facilitates accumulation of mature type 1 conventional dendritic cells, which are required to uniquely prime Ag specific stem-like CD8+ T cells capable of making autocrine IL-2.
In Chapter Four, we use anti-CD4 treatment to induce shared melanocyte/melanoma Ag specific tissue resident memory (TRM) CD8+ T cell responses in skin and lymph nodes of mice that develop melanoma associated vitiligo (MAV). Although previous studies have demonstrated the functional contribution of TRM cells in mediating anti-tumor immunity, they have also indicated that they are transcriptionally heterogenous across different tissues. Moreover, less is known about the signals required to generate and maintain them in discrete tissues in the context of cancer. Thus, in Chapter Four, we explore the temporal and tissue-specific significance of certain signals—TGFb, CD69, IL-7, IL-15, TCR—involved in establishing and sustaining tumor Ag specific TRM cells. Consistent with some studies in viral models, we demonstrate requirements for TGFb, CD69, and IL-7 in generating TRM responses in both LN and skin. Additionally, we show that IL-7 and IL-15 jointly maintain LN and skin TRM cell responses. Lastly, we suggest that LN TRM cells, but not skin TRM cells, rely on TCR signaling to persist.
Recommended Citation
Ramirez, Delaney E., "Investigating the mechanisms for priming and maintaining tumor Ag specific CD8+ T cell responses in the context of CD4-depletion" (2024). Dartmouth College Ph.D Dissertations. 317.
https://digitalcommons.dartmouth.edu/dissertations/317