Rejuvenating endogenous antitumor immunity via a chimeric receptor-engineered oncolytic virus targeting tumor-associated macrophages
(1) Lin C (2) Li S (3) Lou R (4) Teng W (5) Tian Y (6) Feng C (7) Wang N (8) Rao Y (9) Qin Y (10) Li L (11) Huang X (12) Lin Y (13) Zhang J (14) Xia N (15) Huang C
Lin et al. engineered an oncolytic herpesvirus (oHSV) with a PD-L1 nanobody attached to gD on the viral envelope surface (gDαPD- L1), targeting the virus to both tumors and TAMs expressing PD-L1. In addition to its oncolytic activity, this CAR-oHSV also resulted in the presentation of anti-PD-L1 CARs on infected cells, blocking PD-L1 in cis. In TAMs, CAR-oHSV killed a subset of TAMs, while remaining TAMs were reprogrammed via STING activation towards a CXCL9+ antigen-presenting phenotype that supported CD8+ T cell-mediated antitumor immunity. CAR-oHSV was well tolerated and showed synergy with checkpoint blockade and adoptive cell therapy.
Contributed by Lauren Hitchings
(1) Lin C (2) Li S (3) Lou R (4) Teng W (5) Tian Y (6) Feng C (7) Wang N (8) Rao Y (9) Qin Y (10) Li L (11) Huang X (12) Lin Y (13) Zhang J (14) Xia N (15) Huang C
Lin et al. engineered an oncolytic herpesvirus (oHSV) with a PD-L1 nanobody attached to gD on the viral envelope surface (gDαPD- L1), targeting the virus to both tumors and TAMs expressing PD-L1. In addition to its oncolytic activity, this CAR-oHSV also resulted in the presentation of anti-PD-L1 CARs on infected cells, blocking PD-L1 in cis. In TAMs, CAR-oHSV killed a subset of TAMs, while remaining TAMs were reprogrammed via STING activation towards a CXCL9+ antigen-presenting phenotype that supported CD8+ T cell-mediated antitumor immunity. CAR-oHSV was well tolerated and showed synergy with checkpoint blockade and adoptive cell therapy.
Contributed by Lauren Hitchings
ABSTRACT: Immunosuppressive tumor-associated macrophages (TAMs) create a barrier to effective antitumor immunity and promote therapeutic resistance. Reeducating TAMs to enhance their antitumor capabilities through phenotypic remodeling remains challenging. Here, we report a modular oncolytic herpesvirus platform, engineered with a PD-L1-specific chimeric receptor integrated into the viral envelope protein (CAR-oHSV). This design endows the virus with dual tropism, enabling it to target both tumor cells and TAMs within the tumor microenvironment. In virus-resistant tumor models, CAR-oHSV preferentially targets PD-L1(+) TAMs and triggers a STING-dependent reprogramming into a CXCL9(+) phenotype, enhancing their tumor antigen cross-presentation capability and inducing an endogenous antitumor T cell response. Furthermore, this platform can synergize with adoptive T cell therapy and immune checkpoint blockade therapy to overcome immunotherapy resistance. Collectively, our findings define a precision-oncolytic platform that dismantles TAM-mediated immunosuppression while amplifying adaptive immunity, offering a promising translational avenue for cancer immunotherapy.
Author Info:
(1) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institu
te of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (2) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (3) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (4) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (5) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (6) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (7) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (8) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (9) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (10) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (11) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (12) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (13) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (14) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. School of Life Sciences, Xiamen University, Xiamen, 361102, China. (15) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China.
