Date of Award

Spring 4-22-2024

Embargo Period

4-22-2029

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Additional Department

Surgery

College

College of Graduate Studies

Additional College

College of Medicine

First Advisor

Shikhar Mehrotra

Second Advisor

Eduardo Maldonado

Third Advisor

Sophie Paczesny

Fourth Advisor

Laura Kasman

Fifth Advisor

Leonardo Ferreira

Abstract

New approaches to improve adoptive cell therapy (ACT) protocols are needed to enhance persistence of adoptively transferred T cells and overcome tumor-induced immunosuppression and cellular stress. In the first part of this dissertation, we show that exogenous hydrogen sulfide (H2S) can be used to promote the anti-tumor immune response. T cells treated ex vivo with an H2S donor (GYY4137) or overexpressing cystathionine β-synthase (Cbs), which is a key H2S-producing enzyme) display an increase in stemness and antioxidant capacity, enhanced production of cytolytic cytokines and protein translation, and superior tumor control upon ACT using in vivo models of melanoma and lymphoma. Global proteomics analysis revealed that H2S promotes thiolation at key cysteine residues on proteins involved in regulating ER and Golgi function. In the second part of this dissertation, we show that tumor microenvironment-mediated disruption of Golgi architecture and function, termed Golgi stress, can be mitigated by treating anti-tumor T cells with H2S or over-expressing Cbs. We further show that the H2S-induced increase in antioxidant capacity and protein translation is mediated in part by ER-Golgi shuttling of Peroxiredoxin-4. Lastly, we identify that T cells possessing high Golgi content (Golgihi T cells) exhibit unique metabolic and glycation signatures with enhanced anti-tumor capacity. These data demonstrate that strategies to mitigate Golgi network stress or using Golgihi tumor-reactive T cells can improve tumor control upon adoptive transfer.

Rights

Copyright is held by the author. All rights reserved.

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Available for download on Sunday, April 22, 2029

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