Date of Award

1-1-2022

Embargo Period

5-1-2027

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

Eric Bartee

Third Advisor

Bei Liu

Fourth Advisor

Jessica Thaxton

Fifth Advisor

Mark Rubinstein

Sixth Advisor

Gregory Lesinski

Abstract

Adoptive T cell transfer (ACT) therapy improves outcomes in patients with advanced malignancies, yet many individuals relapse due to the infusion of T cells with poor function or persistence. Toll-like receptor (TLR) agonists can invigorate antitumor T cell responses when administered directly to patients, but these responses often coincide with toxicities. We posited that TLR agonists could be repurposed ex vivo to condition T cells with remarkable potency in vivo, circumventing TLR-related toxicity. Herein we reveal a new way to reverse the tolerant state of adoptively transferred CD8+ T cells against tumors using the TLR9 agonist, CpG. We repurposed CpG, commonly used in the clinic, to bolster the ex vivo expansion of T cells for ACT. T cells expanded ex vivo from a CpG-treated culture demonstrated potent antitumor efficacy and prolonged persistence in vivo. This antitumor efficacy was accomplished without in vivo administration of TLR agonists or other adjuvants such as high-dose IL-2 or vaccination, which are classically required for effective ACT therapy. CpG-conditioned CD8+ T cells acquired a unique proteomic signature hallmarked by an IL-2Ralpha high, ICOS high, CD39 low phenotype and an altered metabolic profile. Likewise, human TILs benefitted from expansion with CpG ex vivo, as they also possessed this phenotype. However, CpG did not act directly on T cells in culture but rather via an antigen-presenting cell. B cells were critical in mediating the CpG effects on CD8+ T cells. Both the signature phenotype and antitumor efficacy of CpG-expanded cells were lost when B cells were depleted from the cell culture. CpG fostered the expansion of potent CD8+ T cells by empowering a direct B-T cell interaction. Further, isolated B cells also imparted T cells with the CpG-associated phenotype and improved tumor immunity without the aid of additional APCs or other immune cells in the culture. Our results demonstrate a novel way to use TLR agonists to improve immunotherapy and reveal a vital role for B cells in the generation of potent CD8+ T cell-based therapies. Our findings have immediate implications in the clinical treatment of advanced solid tumors.

Rights

All rights reserved. Copyright is held by the author.

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