CD73 blockade enhances antitumor efficacy of oHSV in solid tumors by increasing macrophage-mediated antigen presentation
Year: 2026
Type: article
Abstract: Background Oncolytic herpes simplex virus (oHSV) therapy is a live virus-based immunotherapy that lyses tumor cells which release antigens and activate antitumor immunity. oHSV therapy has been shown to increase ATP production and release of extracellular ATP (eATP). In the extracellular tumor microenvironment, eATP functions as an immune-activating damage-associated molecular pattern but is hydrolyzed to extracellular adenosine (eADO), which can be immune-suppressive. eADO is generated by the sequential action of ectoenzymes CD39 and CD73 ( NT5E ). Here, we examined the role of immunosuppressive eADO signaling in regulating antitumor immune efficacy of oHSV. Methods We evaluated changes in eADO signaling in vitro and in patient specimens after virotherapy. A genetic CD73 knock-out mouse model and blocking antibodies were used to assess the impact of CD73 on virotherapy in two different solid tumor models. 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. Results Transcriptomic analysis of patient tumors pre-virotherapy and post-virotherapy with CAN-3110 revealed increased expression of the adenosine receptor gene ADORA2B after treatment. High NT5E gene expression, as well as gene signatures suggestive of adenosine signaling, correlated with a significantly worse prognosis for patients with solid tumors. Single-cell sequencing of immune cells recruited to tumor-bearing brain hemispheres in CD73 knockout mice revealed an increase in macrophage-mediated antigen presentation and CD4 + T cell cross-communication. Intracranial tumor-bearing CD73 knock-out mice treated with oHSV showed significant therapeutic improvement as the result of oHSV compared with wild-type mice. Combination of virotherapy with CD73 antibody blockade also resulted in enhanced antitumor efficacy. Conclusions Here, we identify that immunosuppressive eADO signaling in the TME is a major barrier to oHSV therapy and CD73 blockade prevents tumor immune escape. The combination of oHSV with CD73 blockade supports the development of an antitumor immune memory response in solid tumors. This study supports clinical development of this combination strategy.
Institutions: Augusta University, Augusta University Health, The University of Texas Health Science Center at Houston, National Institute of Environmental Health Sciences, National Cancer Institute, Center for Cancer Research, Louisiana State University Health Sciences Center New Orleans, Brigham and Women's Hospital
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
Funders: U.S. Department of Defense, Alliance for Cancer Gene Therapy, Amgen, Cancer Prevention and Research Institute of Texas, Dan L. Duncan Cancer Center, Baylor College of Medicine, Augusta University, University of Texas Health Science Center at Houston, National Institutes of Health, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institute of Dental and Craniofacial Research
Awards: G130627717, G1504377518, G1756901816, G418187648, Proteomics and Metabolomics Core Facility, G5108285509, G5465708471, G5508324684, Targeting the CD73-adenosinergic pathway in head and neck cancer, UTHealth Cancer Genomics Core (UTHealth CGC), G7557813972, G7663504393, G7837447426, G8497683785, G8769334574, G9000240210, Next Gen Virotherapy for GBM, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, Circumventing Barriers to Effective Oncolytic Virotherapy of Malignant Gliomas
OpenAlex ID: W7119512842