Date of Award

4-1-2017

Embargo Period

1-1-2022

Document Type

Thesis - MUSC Only

Degree Name

Master of Biomedical Science

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Chrystal M. Paulos

Second Advisor

Juan C. Varela

Third Advisor

Adam Soloff

Fourth Advisor

Bei Liu

Fifth Advisor

Carl Atkinson

Abstract

Adoptive T cell transfer (ACT) is a promising immunotherapy for patients with cancer, however this approach is not effective for everyone. In part, the rapid ex vivo expansion protocols that diminish T cell antitumor activity prior to transfer influences unsuccessful ACT. In Chapter 1, I provide background on cancer immunotherapies, with an emphasis on adoptive immunotherapy. In Chapter 2 of my thesis, I address our finding that Th17 cells regress large human mesothelioma and murine melanoma tumors when infused into mice, yet it remains unknown the ideal amount of TCR/co-stimulation activation signal strength to generate lymphocytes with durable memory and enhanced functionality. In the clinic, anti-leukemic CD19-CAR T cells are expanded with 3 activating beads to 1 T cell for logarithmic growth, but whether this number of beads is ideal for generating T cells with potent and long-lasting tumor immunity is unclear. To address this question, human Th17 cells were activated with CD3/CD28 or CD3/ICOS-beads with a high (3 beads: 1 T cell), medium (1:10) or low (1:100) ratio. We found stimulating Th17 cells with lower activation signal strength provided greater tumor control and enhanced stemness properties of Wnt/β-catenin and the antiapoptotic protein, Bcl-2, In addition to our findings, stimulation with a high bead to cell ratio increases the glycolytic metabolism. In Chapter 3, we address the question of activation signal strength mediating glucose metabolism to influence the antitumor efficacy in both human Th17 and mouse Pmel-1 cells. We found inhibiting glycolysis enriches central memory populations in both Th17 and CD8+ T cells. Compared to a high or low activation signal strength, 2DG primed Pmel-1 cells more effectively controlled tumor growth. Collectively, our findings are compelling given that most ACT clinical trials use high CD3/CD28 bead activation to expand T cells for cancer treatment. Our novel work reveals high bead activation on T cells diminishes the antitumor activity while lower bead activation fosters stemness properties and lowers glucose metabolism contributing to enhanced antitumor efficacy.

Rights

All rights reserved. Copyright is held by the author.

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