Date of Award

1-1-2016

Embargo Period

1-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Mark Rubinstein

Second Advisor

Zihai Li

Third Advisor

Chrystal Paulos

Fourth Advisor

Chenthamarakshan

Fifth Advisor

Xue-Zhong Yu

Abstract

Adoptive T cell therapy (ACT) has shown promise as a cancer treatment, resulting in cures for many patients who have failed conventional therapies [1-5]. Two potential approaches to further improve ACT response rates are use of polarized T cell subsets, particularly Tc1 and Th17 [6-8], and alleviation of tumor-induced T cell dysfunction. We pursued these two approaches in separate aims, which are linked by their emphasis on the role of IL-2 receptor gamma chain (IL-2Rγ-chain) cytokines, and responsiveness to these cytokines, in the efficacy of T cell-based anti-cancer therapy. We hypothesized that T cells polarized into the Th17 subset are responsive to IL-2Rγ-chain cytokines and that the presence or absence of these cytokines in vivo affects the anti-tumor efficacy of Th17 cells after ACT. In our related investigation of tumor-induced T cell dysfunction, we hypothesized that T cells lose their responsiveness to IL-2Rγ-chain cytokines after prolonged exposure to tumor and that interventions to prevent or reverse T cell dysfunction could therefore synergize with cytokine therapy. Thus our hypotheses were linked by their potential to lead to novel combinatorial cancer therapies involving IL-2Rγ-chain cytokine supplementation along with either adoptive transfer of Th17 polarized T cells or therapies that prevent or reverse T cell dysfunction. IL-2Rγ-chain cytokines (IL-2, IL-7, and IL-15) have important roles in T cell survival, proliferation and functionality [9, 10], giving them the potential to augment ACT [11, 12]. However, the responsiveness of the potent Th17 subset of T cells to these cytokines has not yet been characterized. We found that Th17 cells proliferate in response to IL-2Rγ-chain cytokines in vitro and, in contrast to activated CD8+ T cells, are resistant to IL-2Rγ-chain cytokine withdrawal-induced apoptosis. As further evidence that this novel resistance to cytokine withdrawal-induced apoptosis is related to type 17 polarization, we found that CD8+ Tc17 cells are also resistant to this form of apoptosis. We also found that IL-2 and IL-7, but not IL-15, support the engraftment and anti-tumor activity of Th17 cells in a murine melanoma model. Even after initially successful ACT, tumors can recur. These recurrent tumors contain dysfunctional T cells that can no longer control tumor growth, and express checkpoint receptors, including PD-1 and CTLA-4 [13-18]. While early descriptions of T cell dysfunction focused on inability to respond to antigenic stimuli [19, 20], dysfunctional T cells are also less responsive to cytokines [21-26], including IL-2, IL-7, and IL-15. We created a model of T cell dysfunction in the context of an anti-melanoma immune response, and found that TILs progressively lost the ability to respond to IL-2Rγ-chain cytokines. This loss of cytokine responsiveness was T cell extrinsic but was not prevented or reversed by checkpoint receptor blockade, suggesting that it may have been due to some other inhibitory property of the tumor microenvironment. Finally, we demonstrated that it is possible to significantly slow tumor growth even after the onset of TIL dysfunction by combining cytokine therapy with checkpoint blockade, raising the possibility of novel mechanisms of synergy between these two interventions.

Rights

All rights reserved. Copyright is held by the author.

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