Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Daniel J. Powell Jr.

Abstract

Despite first-line therapy, ovarian cancer (OC) is the 5th leading cause of cancer death in women and is the most lethal gynecological cancer, underscoring the need for improved forms of therapy. Immunotherapies exhibit profound improvements for some cancers; however, efficacy is unimpressive for OC. Both tumor-specific and memory T cells are crucial for efficacious immunotherapies and interrogating their biology in human OC may improve immunotherapeutic strategies for ovarian cancer.Identifying tumor-specific T cells in ovarian tumors is challenging and it is unclear which biomarker (CD137, CD39, CD103, and PD-1) is the most selective in identifying tumor-specific TILs. Mass cytometry analysis found that CD137+ TILs expressed the greatest levels of effector molecules, compared to PD-1+, CD103+ or CD39+ TILs. Removal of CD137+ TILs from PD-1+, CD103+, or CD39+ TILs results in lower secretion of IFNg in response to autologous tumor stimulation, while CD137+ TILs highly secrete IFNg in an HLA-dependent manner. CD137+ TILs exhibited an exhausted phenotype and co-expressed CD28, indicating receptiveness to reinvigoration via immune checkpoint blockade. Overall, our results show that the antitumor abilities of PD-1+, CD103+, and CD39+ TILs are mainly derived from CD137 expressing TILs, supporting that CD137 is a more selective biomarker for tumor-specific TILs.

Furthermore, despite evidence underscoring the importance of stem-cell memory (Tscm) T cells, it is uncertain whether canonical stem cell memory T cells exist in human OC and whether they exhibit antitumor features. Our findings demonstrated that human OC harbors stem cell memory (Tscm) tumor-infiltrating lymphocytes (TILs) and a novel CD45RO expressing Tscm TIL subset. The CD45RO+ Tcsm T cell subset is hierarchically positioned in between CD45RO- (canonical) Tscm T cells and central memory T cells. Notably, the CD45RO+ Tscm T cell subset exhibits a profile indicative of tumor-specificity and effector capabilities, and shares similarities in gene expression and phenotype to T cell subsets in the literature that mediate successful immunotherapy treatment. Taken together, these findings lay the foundation to improve immunotherapy treatments for ovarian cancer patients.

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