All ETDs from UAB

Advisory Committee Chair

Troy Randall

Advisory Committee Members

Troy D Randall

Antonio Di Stasi

Robin G Lorenz

Tim M Townes

Casey T Weaver

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In contrast to chemotherapy and radiotherapy, immunotherapy is able to respond in proportion to tumor burden and continue to evolve in parallel with the tumor mass and metastatic sites. In this way, immune-based cancer therapies are a living drug and hold enormous potential. In this work, we enforce expression of MHCII on a murine breast cancer model to study how changes in tumor biology can drive improved T cell-mediated responses. We next use histone deacetylase inhibitors to manipulate the microenvironment through a more clinically relevant, therapeutic approach. Herein, improvements in tumor control were driven by CD8 T cells and IFNγ, suggesting the in vivo mechanism of these drugs to be distinct from that of impaired tumor cell growth in vitro. In an attempt to reconcile reportedly paradoxical effects of HDAC inhibition, we then propose and demonstrate that the ultimate impact of these agents is wholly dependent on the timing in which treatment is initiated relative to T cell activation status. If appropriately timed, HDAC inhibition can stimulate robust anti-tumor immunity. In this way, we identify timing as a new paradigm and paramount consideration in combinatorial strategies incorporating HDAC inhibitors for the treatment of solid tumors.

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