Inhibition of Urothelial Carcinoma By Type I Interferon Activation of The Innate and Adaptive Immune Response

<p>Bacillus Calmette-Guerin (BCG) is the first line therapy for bladder cancer patients with non-invasive disease. However, roughly 40% of patients exhibit no response, tumor recurrence or tumor progression following BCG treatment. Type I interferon (IFN-I) has potent anti-tumor effects against urothelial carcinoma (UC) and may be an alternative treatment option for patients who do not respond to BCG standard of care. However, the mechanisms that mediate the IFN-I-stimulated immune responses against UC are not fully elucidated. Herein, we evaluated the anti-tumor mechanisms of IFN-I in UC by use of adenoviral interferon-α (Ad-IFNα/Syn3) in human patients, and poly(I:C) or lentiviral IFNa (LV-IFNa) in mice. To this end, I evaluated the IFN-I enhanced immune response by observing increases in expression of immune cell and checkpoint markers in tumors pre- and post- IFN-I treatment. I also characterized the tumor-immune landscape, identified important antitumor effector cells, and described the pathways elicited to recruit the immune response. I found that IFN-I increased the intratumoral levels of Ly6G cells, CD8 T cells, and NK cells, and that the anti-tumor benefit of IFN-I was dependent on IL-6 signaling and multiple immune cell types. I sought to establish therapeutic synergy between IFN-I therapy and PD-1 pathway checkpoint inhibition, and found combination therapy increases survival but is not wholly synergistic, and has additional effect in increasing the immune infiltrate, angiogenesis, and enriching gene signatures of metabolism, extracellular matrix organization, and MAPK/AKT signaling. Altogether, these studies highlight the importance of targeting multiple aspects of the immune response against tumors, and provide a preclinical conceptual example for using type I IFN activation to increase the therapeutic benefit of PD-1 blockade for bladder cancer patients.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2019

Authors dc:creator

• Plote, Devin
• <p><a href="https://www.orcid.org/0000-0002-7715-4142" target="_blank">orcid.org/0000-0002-7715-4142</a></p>

Contributors dc:contributor

• Kim Schluns
• Joya Chandra
• Cullen Taniguchi

• Bladder cancer
• immunotherapy
• Interferon alpha
• urothelial carcinoma
• tumor
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/972

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2021