Targeting Tumor Microenvironmental Factors in Bladder Cancer to Enhance Responses with Immunotherapy
Graduation Year
2024
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Molecular Biosciences
Major Professor
Shari Pilon-Thomas, Ph.D.
Committee Member
Daniel Abate-Daga, Ph.D.
Committee Member
Katarzyna Rejniak, Ph.D.
Committee Member
George Blanck, Ph.D.
Keywords
T cell, acidosis, MDSC, immunosuppression, recurrence
Abstract
Bladder cancer is the tenth most common cancer in the world and has one of the highest recurrence rates. Despite the local delivery options and mutational status of bladder tumors, responses with immunotherapies have been limited with low durability. The bladder tumor microenvironment is enriched with highly immunosuppressive populations and harsh conditions that restrict anti-tumor immunity and subsequently attenuate immunotherapy response. We predict that targeting two of these immunosuppressive components, namely acidity and myeloid derived suppressor cells (MDSCs), will bolster T cell responses and enhance outcomes with immunotherapy. In Chapter 2, we characterized the effects of acidity on T cell function and connected this to activation of TGF-β signaling. We explored neutralization of tumor acidity in vivo using sodium bicarbonate water and found enhancements to T cell immunity and anti-tumor responses. In Chapter 3, we characterized MDSCs and their immunosuppressive effects in bladder cancer patient samples and murine models of bladder cancer. We depleted MDSCs using local delivery of low-dose gemcitabine and induced enhanced anti-tumor responses in combination with local delivery of OT-I T cells. Altogether, we show that targeting acidity and MDSCs in the bladder tumor microenvironment are effective strategies to reinforce T cells responses. We predict that combining these treatment strategies with immunotherapy will reduce recurrences in bladder cancer and increase durability of treatment response.
Scholar Commons Citation
Bazargan, Sarah, "Targeting Tumor Microenvironmental Factors in Bladder Cancer to Enhance Responses with Immunotherapy" (2024). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/11169
