(1) Murphy SA (2) Li J (3) Sahu U (4) Swanner J (5) Lewis CT (6) Anchang B (7) Cui Y (8) Chiocca EA (9) Kaur B
Murphy et al. showed that oncolytic HSV (oHSV) therapy increased extracellular adenosine (eADO) receptor B gene expression in solid tumors, and that worse prognosis correlated with high expression of the gene for the ADO-generating enzyme CD73 and adenosine signaling gene signatures. In solid tumor models, the TME of CD73 KO mice showed increased macrophage-mediated antigen presentation and CD4+ T cell cross-talk, and oHSV-treated CD73 KO mice exhibited greater tumor control than treated WT mice. oHSV plus CD73 Ab blockade increased CD8+ TMEM and TEFF and CD4+ TMEM TILs, and enhanced efficacy and memory.
Contributed by Paula Hochman
(1) Murphy SA (2) Li J (3) Sahu U (4) Swanner J (5) Lewis CT (6) Anchang B (7) Cui Y (8) Chiocca EA (9) Kaur B
Murphy et al. showed that oncolytic HSV (oHSV) therapy increased extracellular adenosine (eADO) receptor B gene expression in solid tumors, and that worse prognosis correlated with high expression of the gene for the ADO-generating enzyme CD73 and adenosine signaling gene signatures. In solid tumor models, the TME of CD73 KO mice showed increased macrophage-mediated antigen presentation and CD4+ T cell cross-talk, and oHSV-treated CD73 KO mice exhibited greater tumor control than treated WT mice. oHSV plus CD73 Ab blockade increased CD8+ TMEM and TEFF and CD4+ TMEM TILs, and enhanced efficacy and memory.
Contributed by Paula Hochman
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.
Author Info: (1) Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, Texas, USA. Pathology, Augusta University Medical College of Georgia, Augusta, G
Author Info: (1) Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, Texas, USA. Pathology, Augusta University Medical College of Georgia, Augusta, Georgia, USA. (2) Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA. Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. (3) Pathology, Augusta University Medical College of Georgia, Augusta, Georgia, USA. (4) Neurosurgery, The University of Texas Health Science Center, Houston, Texas, USA. (5) Neurosurgery, LSU Health New Orleans, New Orleans, Louisiana, USA. (6) Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA. Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. (7) Biochemistry & Molecular Biology, Augusta University Medical College of Georgia, Augusta, Georgia, USA. (8) Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA. (9) Pathology, Augusta University Medical College of Georgia, Augusta, Georgia, USA bkaur@augusta.edu.
Citation: J Immunother Cancer 2026 Jan 8 14: Epub01/08/2026
