Date of Award

2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Andy J. Minn

Abstract

The advent of immune checkpoint blockade (ICB) and other immunotherapies has been a watershed in the evolution of cancer care. Despite these recent breakthroughs, many patients fail to respond to these therapies or relapse after treatment. Recent studies suggest that the availability of effective anti-tumor T cells is limited by cancer immunoediting, which depletes neoantigens that can be recognized by the immune system. Central tolerance further constrains the tumor-specific T cell repertoire by eliminating T cells with high-affinity T cell receptors (TCRs) against potential tumor self-antigens. Self-antigen specific T cells that escape elimination often succumb to exhaustion after ICB; however, whether high-affinity self-reactive T cells could be effectively mobilized to reject ICB refractory tumors is unknown. Through these studies, we test the hypothesis that treatment with a receptor activator of nuclear factor­-κB ligand (RANKL) blocking antibody temporarily disrupts central tolerance leading to the rescue of high-affinity self-reactive T cells that enhance ICB response against neoantigen-poor tumors. We find that transiently interrupting central tolerance through RANKL blockade enabled ICB to durably reject poorly immunogenic tumors. Rejection of ICB refractory B16 melanoma was mediated by CD8 T cells specific for TRP2, a melanoma self-antigen, and coincided with “on-target” autoimmune vitiligo. Murine studies coupled with TCR repertoire analysis revealed that RANKL blockade facilitated the mobilization of a novel population of MFI-high TRP2 tetramer+ CD8 T cells, indicating increased TCR avidity for self-antigen. TRP2 tetramer-high CD8 T cells enriched after RANKL blockade exhibited enhanced TCR signaling, enrichment in NFAT/AP-1 genes, and increased lymph node expansion. In addition, memory-precursor and effector-memory T cells against tumor self-antigens were generated and exhibited transcriptional features associated with clinical ICB response. Furthermore, RANKL blockade enhanced other immunotherapies for cancer, such as therapeutic and prophylactic vaccination. We conclude that RANKL blockade potentiates cancer immunotherapies by expanding the T cell repertoire against tumor self-antigens and thus, facilitates the rejection of otherwise immunotherapy refractory tumors.

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Available to all on Sunday, September 14, 2025

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