Author ORCID Identifier
https://orcid.org/0000-0003-2722-0081
Date of Graduation
12-2025
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Balveen Kaur
Committee Member
Louise McCullough
Committee Member
Michael Curran
Committee Member
Kapil Bhalla
Committee Member
Jason Huse
Abstract
Oncolytic HSV (oHSV) therapy is a live virus-based immunotherapy that lyses tumor cells which release antigens and activate anti-tumor immunity. Immunotherapy-based drugs have made significant advances in treating cancer. However, unchecked immune activation can escalate to autoreactivity or toxicity, so this inflammation is frequently accompanied by anti-inflammatory responses to maintain tissue homeostasis. Tumor cells can exploit anti-inflammatory pathways to escape anti-tumor immune responses. Here we identify that oHSV immune therapy rewires the tumor microenvironment to take advantage of immunosuppressive extracellular adenosine (eADO) signaling as a means of escaping host anti-tumor immune responses. Transcriptomic analysis of patient tumors pre- and post-virotherapy with CAN-3110 revealed increased expression of the adenosine receptor gene ADORA2B after treatment. The accumulation of eADO in the TME is predominantly the responsibility of ectoenzyme CD73 (NT5E) which catalyzes the hydrolysis of AMP to eADO. High NT5E gene expression, as well as gene signatures suggestive of adenosine signaling, correlated with a significantly worse prognosis for patients with solid tumors. Here, we examine the impact of blocking CD73 on therapeutic response to oHSV in immune competent solid tumor models. Tumor-bearing CD73 global knock-out mice treated with oHSV and wild type mice treated with a murine CD73 antibody and oHSV showed significant improvements in therapeutic efficacy of oHSV. Single cell RNA sequencing was employed to assess changes in immune cell infiltration and communication. Flow cytometric immunophenotyping and immunofluorescent imaging were utilized to confirm single cell sequencing predicted changes in tumor microenvironment. Sequencing data and in vivo blockade of myeloid cell recruitment into tumors revealed that this beneficial therapeutic effect partially relies on increased macrophage mediated antigen presentation. The combination of oHSV with a function-blocking CD73 antibody supports the development of an anti-tumor immune response in solid tumors. We then isolated and characterized a novel, function blocking, human CD73 antibody by screening a human phage display library. This antibody reduces virus-induced eADO and improves anti-tumor responses of cultured human immune cells. To evaluate the efficacy of Ab6, we created humanized mice and observed significant anti-tumor efficacy of Ab6 in combination with oHSV. These studies support the further development of Ab6 for safety and efficacy studies in patients.
Recommended Citation
Murphy, Sara A., "Inhibition of adenosinergic signaling in the tumor immune environment: the effect of combination CD73 blockade and oHSV therapy on solid tumors" (2025). Dissertations & Theses (Open Access). 1505.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1505
Keywords
oncolytic virus therapy, oHSV therapy, oHSV, oncolytic herpes virus, CD73, adenosine signaling, solid tumor, glioblastoma, tumor microenvironment, antibody, immune therapy