UNCOVERING THE ROLE OF CD38 IN T CELLS

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Degree type
Doctor of Philosophy (PhD)
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Cell and Molecular Biology
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Biology
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01/01/2024
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Veliz, Kimberly
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Abstract

CD38 is a multifunctional cell surface molecule expressed on lymphocytes, known for its ecto-enzymeactivity in metabolizing NAD to cADPR and ADPR. Its increased expression on T cells can inhibit function through two proposed pathways. Firstly, it generates immunosuppressive adenosine by converting NAD to ADPR, further metabolized to AMP and then adenosine. Secondly, it regulates the NAD-Sirt1-FOXO pathway, impacting T cell metabolism and anti-tumor response. My findings indicate that CD38 expression on T cells is higher and sustained longer compared to other immune checkpoint receptors when stimulated. This suggests a unique role for CD38 distinct from other inhibitory molecules. In short-term killing assays, CD38 knock-out (CD38KO) T cells killed tumor cells similarly to PD1 knock-out (PD1KO) T cells. Moreover, in re-stimulation models, CD38KO T cells exhibited enhanced tumor cell killing and comparable cytokine secretion to PD1KO T cells. Transiently upregulated cell surface molecules on activated T cells can inhibit function, prompting investigation into deleting or blocking immune checkpoint receptors to enhance engineered immune effector cells. Despite CD38’s upregulation on activated T cells, its inhibitory role remains unclear. Compared to PD1, CTLA4, LAG3, and TIM3, CD38 displays sustained and intense expression postactivation. Deleting CD38 from CAR T cells confers resistance to exhaustion in vitro and improved anti-tumor function in vivo. Reconstitution experiments with CD38 mutants reveal its necessity in adenosine production and NAD consumption, suggesting a role for CD38 as an immunometabolic checkpoint in T cells and proposing CD38 deletion as a strategy for boosting CAR T cell function.

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Carreno, Beatriz, M
Date of degree
2024
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