Advisor(s)

Masakazu Kamata

Committee Member(s)

Allan Zajac
Gurkan Mollaoglu
Jianmei Leavenworth
Lewis Shi

Document Type

Dissertation

Date of Award

6-18-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Microbiology

Abstract

The potent cytotoxic activity of T cells serves as a natural defense against cancers. Chimeric antigen receptor (CAR) T cell therapy represents a strategy for harnessing T cells against advanced tumors. CAR-T cell therapy has seen striking success against hematologic malignancies, prompting its application to new diseases. Ovarian cancer is a highly lethal disease characterized by frequent recurrence and aggressive nature, prompting the investigation of CAR-T cell therapy as a salvage regimen. However, like in other solid tumors, the early performance of CAR-T cell therapy in ovarian cancer is poor. While many strategies exist for improving the longevity of CAR-T cells or mitigating suppression in the tumor environment, few options exist for intrinsically improving the cytotoxic functionality of CAR-T cells. Recognizing the role of nuclear factor of activated T cells (NFAT) signaling in governing T cell functionality, I hypothesized that regulation of NFAT signaling through the c-Jun N-terminal Kinases (JNK) pathway impacts CAR-T cell effector function. I here develop a CAR vector that induces stable JNK knockdown and characterize the impacts to CAR-T cell performance using primary human T cells from healthy donors. CAR-T cell functionality was assessed in vitro and in xenograft models of human ovarian cancer. JNK knockdown did not impact the differentiation status of CAR-T cells or in vivo persistence, but enhanced CAR-T cell cytotoxicity through elevations in granzyme B expression and degranulation. These changes were associated with and dependent on changes to NFATc1 signaling, highlighting a link between NFAT, JNK, and CAR-T cell effector function. JNK knockdown represents a novel strategy for enhancing CAR-T cell potency which may be combinable with existing CAR-T cell strategies, potentially unlocking efficacy in solid tumors like ovarian cancer.

Keywords

Chimeric antigen receptor - CAR;Immunotherapy;Ovarian Cancer;T cell

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