Oncolytic vaccinia virus armed with 4–1BBL elicits potent and safe antitumor immunity and enhances the therapeutic efficiency of PD-1/PD-L1 blockade in a pancreatic cancer model

Yushi Ju; Feiyu Dai; Yirong Wang; Zhenyu Ye; Yang Li; Songguang Ju; Yan Ge; Wei Chen

Translational Oncology (Dec 2024)

Oncolytic vaccinia virus armed with 4–1BBL elicits potent and safe antitumor immunity and enhances the therapeutic efficiency of PD-1/PD-L1 blockade in a pancreatic cancer model

Yushi Ju,
Feiyu Dai,
Yirong Wang,
Zhenyu Ye,
Yang Li,
Songguang Ju,
Yan Ge,
Wei Chen

Affiliations

Yushi Ju: Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province 215004, China
Feiyu Dai: Department of Immunology, Basic Medical College, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China; Medical Biotechnology Institute, Soochow University, Suzhou, Jiangsu 215123, China; Collaborative Innovation Center of Bone and Immunology between Sihong Hospital and Soochow University, Suzhou 215123, China
Yirong Wang: Department of Immunology, Basic Medical College, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China; Medical Biotechnology Institute, Soochow University, Suzhou, Jiangsu 215123, China; Collaborative Innovation Center of Bone and Immunology between Sihong Hospital and Soochow University, Suzhou 215123, China
Zhenyu Ye: Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province 215004, China
Yang Li: Department of Immunology, Basic Medical College, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China; Medical Biotechnology Institute, Soochow University, Suzhou, Jiangsu 215123, China; Collaborative Innovation Center of Bone and Immunology between Sihong Hospital and Soochow University, Suzhou 215123, China
Songguang Ju: Department of Immunology, Basic Medical College, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China; Medical Biotechnology Institute, Soochow University, Suzhou, Jiangsu 215123, China; Collaborative Innovation Center of Bone and Immunology between Sihong Hospital and Soochow University, Suzhou 215123, China; Corresponding authors.
Yan Ge: Department of Immunology, Basic Medical College, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China; Medical Biotechnology Institute, Soochow University, Suzhou, Jiangsu 215123, China; Collaborative Innovation Center of Bone and Immunology between Sihong Hospital and Soochow University, Suzhou 215123, China; Corresponding authors.
Wei Chen: Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province 215004, China; Corresponding authors.

Journal volume & issue: Vol. 50
p. 102151

Abstract

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Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a poor prognosis. Mono-immunotherapy, such as blockade of the PD-1/PD-L1 pathway, for PDAC has proven to be less effective. The systemic exertion of 4–1BB signaling enhanced antitumor immunity accompanied by hepatotoxicity, which is an obstacle for its clinical application. Our study exploits an oncolytic virus armed with 4–1BBL (VV-ΔTK-4L) to locally express 4–1BBL in the tumor microenvironment (TME), thus avoiding hepatotoxicity. VV-ΔTK-4L prolonged the survival time of a pancreatic tumor mouse model and modified the immune status of the TME and spleen. In the TME, the quantities of CD45+ cells, NK1.1+ cells, CD11c+ DCs, CD3+ T, CD4+ T, and CD8+ T cells increased. Compared to VV-ΔTK treatment, VV-ΔTK-4L further increases the number of CD8+ T cells with effector phenotypes, and downregulates exhaustion-related molecules on CD8+ T cells, and does not increase the proportion of Foxp3+ T cells. Thus, the TME of pancreatic cancer was converted from “cold” to “hot” by VV-ΔTK-4L. Blockade of the PD-1/PD-L1 pathway combined with VV-ΔTK-4L further significantly improves the survival ratio of a tumor-bearing mouse model. This study provides a systemic therapeutic strategy and approach for PDAC immunotherapy.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

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