Tumor-Intrinsic Mechanisms of Immune Evasion and Metabolic Reprogramming for T Cell Immunotherapy

Date of Award

Spring 2022

Document Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Chen, Sidi


Immune evasion is a critical step of cancer progression that can occur through tumor-intrinsic and extrinsic mechanisms. Tumor-intrinsic mechanisms such as immune checkpoints have been promising targets for immunotherapy; However, there remain fundamental gaps in our understanding of immune evasion, as well as unexplored strategies to improve current immunotherapies. We hypothesized that we can identify novel genetic factors that mediate immune escape by leveraging in vivo tumorigenesis screens in hosts with different levels of immunocompetence. Specifically, parallel high-throughput genetic knock-out screens were performed in immortalized hepatocytes that are able to generate tumors in immunocompromised but not wild-type mice to determine which genes enable immune escape when a complete immune system is present. Our screen identified Prkar1a as a strong tumor suppressor gene, while phospho-proteomics, single-cell transcriptomics, and functional characterization of the Prkar1a tumor microenvironment (TME) revealed tumor-intrinsic mechanisms of immune escape, such as pro-inflammatory signaling and extracellular matrix remodeling, as well as the tumor-extrinsic mechanism of recruiting immunosuppressive polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Next, we sought to exploit a common tumor-intrinsic immune escape mechanism, whereby cancer cells suppress T cell function by targeting its cellular metabolism. More specifically, we hypothesized that we could modify the gene expression of TME-related metabolic enzymes and screen for improved T cell function. We identified candidate metabolic regulatory enzymes with an in-silico screen, and demonstrate that genetic overexpression of Adenosine Deaminase (ADA) can enhance anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy, by increasing T cell cytotoxicity and proliferation, while decreasing exhaustion. Collectively, these projects reveal new knowledge at the intersection of cancer biology and immunity, as well as reveal new avenues to pursue in immunotherapeutic research.

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