Date of Award

1-1-2017

Embargo Period

1-1-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Chrystal Paulos

Second Advisor

Ramsay Camp

Third Advisor

Laura Kasman

Fourth Advisor

Zihai Li

Fifth Advisor

Shikhar Mehrotra

Abstract

Cancer immunotherapies engage the immune system to elicit antitumor responses. The discovery of cell-intrinsic inhibitory pathways and cancer-specific antigens has allowed for the advancement of immune checkpoint blockades and a cellular therapy called adoptive cell transfer (ACT), respectively. ACT is an innovative therapy that entails the acquisition, expansion and infusion of autologous T cells back into the patient to eradicate tumors. The development of this field has yielded exciting results for patients with advanced malignancies, particularly blood-based cancers. Defined as a living drug, ACT has the unique potential to elicit long-term responses if transferred T cells are capable of persisting. While CD8+ T lymphocytes mediate potent immune responses against tumor, the role of human CD4+ T cell subsets in cancer immunotherapy remains ill defined. Herein, we exhibit that CD26 identifies three T helper subsets with distinct immunological properties in both healthy individuals and cancer patients. While CD26neg T cells possess a regulatory phenotype, CD26int T cells are mainly naïve and CD26high T cells appear terminally differentiated and exhausted. Paradoxically, CD26high T cells regress multiple solid tumors and persist long-term following adoptive cell transfer. Further analysis revealed that CD26high cells have a rich chemokine receptor profile (including CCR2 and CCR5), profound cytotoxicity (Granzyme B and CD107A), resistance to apoptosis (c-KIT and Bcl2) and enhanced stemness (β-catenin and Lef1). These properties license CD26high T cells with a natural capacity to traffic to, regress and survive in solid tumors. Furthermore, we discovered a direct correlation between the percentage of CD26+ TIL and overall tumor response. While this finding suggests that CD26 may be playing a direct role in the antitumor activity of CD4+ T cells, we found that this was not the case as pharmaceutical inhibition of enzymatic activity or complete deletion of CD26 did not diminish the function, phenotype, persistence or antitumor activity of murine or human Th17 cells. Therefore, CD26 appears to be a correlative marker that can identify therapeutic T cells. Thus, this dissertation identifies both a unique CD4+ T cell subset with enhanced antitumor activity, as well as a potential biomarker for selecting therapeutic T cells.

Rights

All rights reserved. Copyright is held by the author.

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