Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical models. In the clinic, upregulation of JAG1 gene expression was observed in recurrent high-grade glioma patients treated with CAN-3110. Since JAG1 is expressed on both glioma cells and tumor-associated macrophages (TAMs), and its expression correlated with a worse prognosis, we engineered a JAG1-antagonizing oHSV (OncoD-0J1) and interrogated its impact on the tumor and myeloid TME. OncoD-0J1 antagonized JAG1-mediated Notch signaling and had a significant therapeutic advantage in vivo, which relied on Notch signature in tumor cells. Kinome profiling revealed that OncoD-0J1 treatment suppressed CDK1, resulting in a G2/M cell cycle checkpoint as seen by cell cycle analysis. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62 accumulation, autophagosome accumulation, and senescence-associated beta-galactosidase activity. This resulted in increased production of inflammatory chemokines and DAMPs such as IL-1β and extracellular ATP. RNA sequencing of murine macrophages co-cultured with infected human tumor cells showed enrichment of chemotactic and pro-inflammatory pathways as well as increased Fc receptor activation following OncoD-0J1 infection. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from infected tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OncoD-0J1 treatment. Senescent cells showed heightened EGFR activation as a mechanism to escape death, which created a unique vulnerability for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the anti-tumor therapeutic response of OncoD-0J1 as a monotherapy.
","abstract_html":"<p>Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical models. In the clinic, upregulation of JAG1 gene expression was observed in recurrent high-grade glioma patients treated with CAN-3110. Since JAG1 is expressed on both glioma cells and tumor-associated macrophages (TAMs), and its expression correlated with a worse prognosis, we engineered a JAG1-antagonizing oHSV (OncoD-0J1) and interrogated its impact on the tumor and myeloid TME. OncoD-0J1 antagonized JAG1-mediated Notch signaling and had a significant therapeutic advantage in vivo, which relied on Notch signature in tumor cells. Kinome profiling revealed that OncoD-0J1 treatment suppressed CDK1, resulting in a G2/M cell cycle checkpoint as seen by cell cycle analysis. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62 accumulation, autophagosome accumulation, and senescence-associated beta-galactosidase activity. This resulted in increased production of inflammatory chemokines and DAMPs such as IL-1β and extracellular ATP. RNA sequencing of murine macrophages co-cultured with infected human tumor cells showed enrichment of chemotactic and pro-inflammatory pathways as well as increased Fc receptor activation following OncoD-0J1 infection. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from infected tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OncoD-0J1 treatment. Senescent cells showed heightened EGFR activation as a mechanism to escape death, which created a unique vulnerability for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the anti-tumor therapeutic response of OncoD-0J1 as a monotherapy.</p>","abstract_has_math":false,"creators":["Rivera Caraballo, Kimberly Ann","https://orcid.org/0000-0001-9275-7286
"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Balveen Kaur","Ji Young Yoo","Jian Hu"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-05-01T07:00:00Z","date_published":"2025-05-01T07:00:00Z","updated_at":"2026-07-24T05:50:47Z","subjects":["glioblastoma","oncolytic virotherapy","oncolytic HSV-1","Notch signaling","senescence","macrophages","tumor microenvironment","Cancer Biology","Cell Biology","Immunotherapy"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1429","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Balveen Kaur","Ji Young Yoo","Jian Hu"]},{"key":"dc:creator","label":"Author","values":["Rivera Caraballo, Kimberly Ann","https://orcid.org/0000-0001-9275-7286
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"]},{"key":"dc:title","label":"Title","values":["JAG1 Blockade With oHSV Polarizes Macrophages to Create a Unique Vulnerability for Cetuximab-Mediated Senolysis of Glioma Cells"]}]}],"canonical_facts":{"dc:contributor":["Balveen Kaur","Ji Young Yoo","Jian Hu"],"dc:creator":["Rivera Caraballo, Kimberly Ann","https://orcid.org/0000-0001-9275-7286
"],"dc:date.available":["2027-04-25T07:00:00Z"],"dc:description.abstract":["Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical models. In the clinic, upregulation of JAG1 gene expression was observed in recurrent high-grade glioma patients treated with CAN-3110. Since JAG1 is expressed on both glioma cells and tumor-associated macrophages (TAMs), and its expression correlated with a worse prognosis, we engineered a JAG1-antagonizing oHSV (OncoD-0J1) and interrogated its impact on the tumor and myeloid TME. OncoD-0J1 antagonized JAG1-mediated Notch signaling and had a significant therapeutic advantage in vivo, which relied on Notch signature in tumor cells. Kinome profiling revealed that OncoD-0J1 treatment suppressed CDK1, resulting in a G2/M cell cycle checkpoint as seen by cell cycle analysis. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62 accumulation, autophagosome accumulation, and senescence-associated beta-galactosidase activity. This resulted in increased production of inflammatory chemokines and DAMPs such as IL-1β and extracellular ATP. RNA sequencing of murine macrophages co-cultured with infected human tumor cells showed enrichment of chemotactic and pro-inflammatory pathways as well as increased Fc receptor activation following OncoD-0J1 infection. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from infected tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OncoD-0J1 treatment. Senescent cells showed heightened EGFR activation as a mechanism to escape death, which created a unique vulnerability for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the anti-tumor therapeutic response of OncoD-0J1 as a monotherapy.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1429"],"dc:subject":["glioblastoma","oncolytic virotherapy","oncolytic HSV-1","Notch signaling","senescence","macrophages","tumor microenvironment","Cancer Biology","Cell Biology","Immunotherapy"],"dc:title":["JAG1 Blockade With oHSV Polarizes Macrophages to Create a Unique Vulnerability for Cetuximab-Mediated Senolysis of Glioma Cells"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:50:47Z"}