Enzyme-mediated methylthioadenosine depletion as a novel immune checkpoint therapy

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2021-05

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Methylthioadenosine phosphorylase (MTAP) is an enzyme that is homozygously deleted in approximately 15% of all human cancer types. MTAP deletion has been correlated with cancer progression, poor patient survival, and resistance to immune checkpoint therapies. Frequent MTAP loss in cancer leads to the accumulation of its substrate 5’-deoxy-5’-methylthioadenosine (MTA), which exerts potent immunosuppressive effects in T cells. We hypothesize that accumulated MTA in the tumor microenvironment of MTAP-deficient tumors induces an immunomodulatory effect on surrounding T cells and engenders tumor tolerance. In this dissertation, we explore the therapeutic efficacy of enzyme-mediated MTA depletion in several MTAP-deficient tumor models. Our results indicate that treating MTAP-deficient tumors with MTA-degrading enzymes can drastically suppress tumor growth. Moreover, our in vivo studies and immunophenotyping experiments suggest that the therapeutic benefit of MTA-depletion is mediated by CD8 T cells that infiltrate the tumor microenvironment. Additionally, we tested the combined therapeutic effects of MTA depletion with immune checkpoint therapy (e.g., anti-PD1 or anti-CTLA4) and observed a potent synergistic effect. Furthermore, we investigate MTA’s mechanism of action on T cells. Due to MTA’s structural similarities with adenosine, we examined putative signaling of MTA through adenosine receptors. Our findings show that adenosine signaling is not the main pathway that MTA utilizes to suppress T cells. Instead, our proteomics analysis of T cells incubated with MTA suggest that MTA inhibits T cells, at least in part, via the differential expression of methyltransferase/demethylase enzymes, upregulation of proapoptotic proteins, and inhibition of proteins crucial for TCR activation and cytokine signaling. In this work, we also discuss the engineering and optimization of the MTAP enzyme for therapeutic use. Collectively, this dissertation elucidates the suppression mechanism of MTA on T cells and demonstrates the potential of utilizing MTA-depletion therapy as a biomarker-driven (namely, MTAP status) immunotherapeutic modality.

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