Date on Master's Thesis/Doctoral Dissertation

12-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Cooperating University

University of Louisville

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Yaddanapudi, Kavitha

Committee Member

Mitchell, Thomas

Committee Member

Bodduluri, Haribabu

Committee Member

Jala, Venkatakrishna

Committee Member

Donninger, Howard

Author's Keywords

enzymatic; depletion; adenosine; cancer; immunotherapy; potentiate

Abstract

Immune checkpoint blockade (ICB) therapies have revolutionized cancer treatment, but many patients still do not respond well. To improve therapeutic outcomes, chemotherapy is often combined with immunotherapy, as chemotherapy is known to promote immunogenicity. However, many patients develop resistance to this combination therapy, and the reasons behind it are not fully understood. In this study, we explored how platinum-based chemotherapy, specifically cisplatin, affects tumor signaling to create an immunosuppressive tumor microenvironment (TME). We found cisplatin triggers ataxia telangiectasia mutated (ATM)-mediated DNA damage signaling and induces higher expression of prostaglandin E₂ (PGE₂) via a cyclooxygenase-2 (COX-2) mediated pathway. We speculate DNA damage signaling is linked to higher level of COX-2 expression. Importantly, we discovered PGE₂ induces CD73 expression on monocytic myeloid-derived suppressor cells (M-MDSCs) via activating STAT3 and CREB signaling. CD73 converts AMP into adenosine which suppresses CD8⁺ T-cell activity and promotes immunosuppression. These results show that chemotherapy can paradoxically cause the TME to become more immunosuppressive, reducing the effectiveness of chemoimmunotherapy combinations. As high PGE₂ levels result in adenosine-mediated immunosuppression, we used PEGylated adenosine deaminase (PEG-ADA) to convert adenosine to the immunostimulant inosine. This treatment restored T-cell function, as evidenced by reduced tumor volume, decreased adenosine level and increased CD8+IFNg+ in mice treated with PEG-ADA. Therefore, adding PEG-ADA to chemo-immunotherapy regimens could be a promising strategy to improve treatment response in solid tumors.

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