All ETDs from UAB

Advisory Committee Chair

Troy D Randall

Advisory Committee Members

Rebecca C Arend

Andre Ballesteros-Tato

Laurie E Harrington

Anita B Hjelmeland

Alexander Rosenberg

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The omentum is an adipose tissue in the peritoneal cavity that contains immune aggregates termed milky spots. Functionally similar to conventional lymphoid tissues, these specialized leukocyte clusters harbor effector and suppressor cells, mount immune responses to antigens, and sustain peritoneal homeostasis. However, the pre-existing leukocytes fail to protect the tissue from tumor colonization. In fact, the omentum is frequently involved in peritoneal metastasis, during which the balance between effector and suppressor immune cells is compromised with the latter gaining dominance. Regulatory T cells (Tregs) represent a major immunosuppressive population in the omentum and rapidly accumulate after tumor implantation. The increased Treg abundance may be attributed to the local proliferation of pre-existing Tregs, peripheral Treg conversion, and/or cell recruitment from the circulation. Using T cell receptor (TCR) repertoire analysis, we show that tumor progression in the omentum does not promote Treg clonal expansion but leads to the influx of small Treg clonotypes. Naive CD4+ T cells poorly differentiate to Tregs in tumor-bearing omenta, suggesting a minimal contribution of peripheral conversion to the enlargement of the omental Treg pool. Parabiosis experiments reveal that circulating Tregs robustly migrate to the omentum as tumors progress, wherein they metabolically adapt to the environment and acquire the transcriptional signature of adipose-resident Tregs. We then find that CXCR3 is essential for Treg recruitment to omental tumors, and that CD4-specific CXCR3 ablation abrogates Treg accumulation and enhances tumor control. Interestingly, CXCR3 also supports effector CD8+ T cell responses, which mediate tumor control. Without this chemokine receptor, CD8+ T cells fail to undergo proper effector differentiation and maintain their numerical abundance in omental tumors. Therefore, our data reveal the mechanisms for the accumulation of Tregs and CD8+ T cells in omental tumors and uncover the pivotal roles of CXCR3 in this process.

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