Defense Date

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Integrative Life Sciences

First Advisor

Paula D. Bos, Ph.D.

Second Advisor

John J. Ryan, Ph.D.

Third Advisor

Christopher Lemmon, Ph.D.

Fourth Advisor

Senthil Radhakrishnan, Ph.D.

Fifth Advisor

Azeddine Atfi, Ph.D.

Abstract

Transient ablation of regulatory T cells has been shown to be effective at hindering tumor growth and metastasis in murine breast cancer model. Based on our lab’s previous work, we have demonstrated that NK cells and CD8+ cytotoxic T cells were not required for the protective effect of Treg cell ablation. However, we also reported that CD4+ helper T cells and IFN-γ were required for the protective effect of Treg cell ablation. Furthermore, we observed that CD11B+ cells responded to Treg ablation therapy by up-regulating target genes of IFN-γ. Therefore, this study aimed to investigate the connection between the myeloid cell compartment and IFN-γ signaling after regulatory T cell ablation therapy. Through a combination of conditional knockout mouse models, cellular fate mapping experiments, adoptive transfers, and co-injection experiments, we demonstrated that tumor-associated macrophages (TAMs), derived from the bone marrow via CCR2/CCL2 axis, were responsible for the therapeutic effect of regulatory T cell ablation. In addition, we determined that IFN-γ signaling was required for the TAMs to mediate the protective phenotype seen after regulatory T cell ablation. Furthermore, based on our findings, we developed a genetic signature based on TAMs from treated or untreated tumors that had a predictive value for patient survival. Thus, our findings indicated a strong connection between IFN-γ release, classical activation of TAMs, and depletion of regulatory T cells, and taken together, our data could offer potential clinical strategies to mimic regulatory T cell ablation.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-8-2019

Available for download on Saturday, May 04, 2024

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