Graduation Date

Summer 8-14-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Pankaj Kumar Singh

Abstract

Metabolic and immune alterations are ubiquitous hallmarks of cancer that are established during the foundational mutations and are further selected upon to generate highly aggressive tumors. Recent evidence suggests that cancer cells employ an altered metabolism to induce immune evasion. To further discover the relationship between metabolism and immunity in cancer, this thesis aimed to discover potential candidates of interest by first examining the mucin family for differences, as they exert a wide range of activities in cancer, including altered metabolism and immune alterations. Unique differences lead to further profiling in pancreatic and esophageal cancer. In pancreatic cancer, CD73 was discovered to have a large significant impact on patient survival, which was recapitulated in vivo and postulated to exert immune suppression through a GM-CSF, MDSC, and CD4+ axis. This metabolic control was seen to ablate tumor growth and can severely limit growth when inhibiting CD73 in combination with gemcitabine. To further examine the potential effect of metabolic differences in cancer, esophageal cancer was further explored, as it contained to have two largely different metabolic profiles. Here, the largest pathway difference was discovered to be immune alterations. These two subtypes appeared to have many immune differences, including immune infiltration, cytokine profiles, and predicted response to checkpoint therapy. Lastly, the study sought to find the enzymes that had the highest correlation with a transcriptional immune dysfunction signature in order identify other potential metabolic enzymes to target to prevent immune evasion.

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