Date of Award

2021

Embargo Period

1-1-2026

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Chrystal Paulos

Second Advisor

Gregory Lesinski

Third Advisor

Zihai Li

Fourth Advisor

Shikhar Mehrotra

Fifth Advisor

David Neskey

Sixth Advisor

Mark Rubinstein

Abstract

Adoptive transfer of tumor-reactive T cells (ACT) is an effective therapy for patients with aggressive, metastatic malignancies. ACT has resulted in objective responses in 50-90% of patients, with a proportion of those responding durably for multiple years. Because T cells are expanded in culture for multiple weeks prior to infusion into the patient, this protocol drives high cost, treatment delays, and often generates sub-optimal T cells which leads to relapse. Therefore, novel approaches of generating therapeutic T cells rapidly are of clinical interest. We hypothesized that the T cell expansion process could be abbreviated by enriching CD4+ Th17 cells—a specific subset endowed with potent antitumor properties. Shortening ex vivo expansion to only four days licensed both murine and human Th17 cells to eradicate solid tumors to a greater extent than cells expanded long-term, despite compromised cell yield. We identified two novel mechanisms through which Day 4 Th17 cells ablate tumors in immunocompetent hosts. First, Day 4 Th17 cells induced multiple cytokines in the host including IL-6, IL-17, and MCP-1, and they persisted as memory cells. IL-6 was critical for therapy efficacy and for protection against tumor relapse. Mechanistically, IL-6 promoted survival of donor Th17 cells and diminished engraftment of regulatory T cells (Tregs), ultimately allowing robust infiltration of Th17 cells over Tregs into the tumor. Collectively, we highlight an underappreciated role for IL-6 in promoting durable immunity to cancer. We next hypothesized that host immune cells cooperated with infused Th17 cells to eradicate tumors. Surprisingly, host B cells, but not CD8+ T cells, were critical to Th17 immunity. While B cells were not the source of IL-6, Th17 cells promoted B cell activation and antibody secretion. B cells activated donor Th17 cells, fostered their inflammatory phenotype, and supported persistence. Our work implicates MHC-II, ICOS, IFN-γ, and IL-21 as key players in this mechanism. Overall, this dissertation reveals that therapeutic Th17 cells can be generated after a short ex vivo expansion period, and identifies a novel role for IL-6 and B cells in eliciting long-term efficacy for Th17 cell therapies. These findings have implications for harnessing effective Th17 immunity in patients.

Rights

All rights reserved. Copyright is held by the author.

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