Journal for immunotherapy of cancer · 2026
Oncolytic virotherapy potentiates chemo-PD-1 immunotherapy by engaging chemo-resistant bystander CD8+ T cells.
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Yang Yang, He Junjian, Liang Texi, Li Kaiyi, Lin Yao, Wang Hairu, Xi Wenwen, Ye Shusen, Qiu Ding, Xie Chunyang, Hao Yaxing, Li Teming, Yue Shuai, Ye Lilin, Chen Xiangyu
Аннотация
BACKGROUND: The efficacy of combined chemotherapy and programmed cell death protein-1 (PD-1) immune checkpoint blockade (ICB) is constrained by the collateral cytotoxicity of chemotherapy toward proliferating tumor-specific CD8+ T (TTST) cells, a population indispensable for antitumor immunity. This study aimed to overcome this limitation by targeting a potential chemotherapy-resistant immune cell reservoir.
METHODS: By using the murine acutely resolved lymphocytic choriomeningitis virus (LCMV) infection and tumor models (colorectal cancer and melanoma), we characterized the susceptibility of CD8+ TTST and virus-specific bystander memory CD8+ T (TBYS) cells to platinum-based chemotherapy-induced cytotoxicity. We next evaluated the antitumor efficacy and underlying mechanisms of combined chemotherapy and TBYS cell-targeted oncolytic virus therapy (OV-BYTE) in tumor-bearing mice with prior LCMV infection or SARS-CoV-2 vaccination. Finally, we assessed the antitumor efficacy of the triple combination regimen (including OV-BYTE, chemotherapy, and PD-1 ICB) in both murine colorectal cancer model and patient-derived colorectal cancer organoid.
RESULTS: We first demonstrated that within the tumor microenvironment, CD8+ TTST cells are highly susceptible to platinum-based chemotherapy, whereas CD8+ TBYS cells constitute a quiescent, chemo-resistant population. Leveraging this, CD8+ TBYS-targeted OV-BYTE therapy synergized with chemotherapy to control tumorigenesis in multiple murine models. Mechanistically, this dual combination directly engaged the CD8+ TBYS cell reservoir for tumor killing, which was accompanied by the restoration of CD8+ TTST cell function via reduced apoptotic susceptibility and acquisition of a polyfunctional, effector-like state. Consequently, integrating OV-BYTE into the standard chemo-PD-1 ICB regimen resulted in improved antitumor efficacy in both preclinical and patient-derived tumor models.
CONCLUSIONS: Our study establishes the chemotherapy-resistant CD8+ TBYS cell niche as a pivotal therapeutic target. By engaging this target, OV-BYTE emerges as a potent combinatorial agent that successfully circumvents a core limitation of standard chemo-immunotherapy, thus offering a rationally designed and translatable strategy to advance combination cancer therapy.
METHODS: By using the murine acutely resolved lymphocytic choriomeningitis virus (LCMV) infection and tumor models (colorectal cancer and melanoma), we characterized the susceptibility of CD8+ TTST and virus-specific bystander memory CD8+ T (TBYS) cells to platinum-based chemotherapy-induced cytotoxicity. We next evaluated the antitumor efficacy and underlying mechanisms of combined chemotherapy and TBYS cell-targeted oncolytic virus therapy (OV-BYTE) in tumor-bearing mice with prior LCMV infection or SARS-CoV-2 vaccination. Finally, we assessed the antitumor efficacy of the triple combination regimen (including OV-BYTE, chemotherapy, and PD-1 ICB) in both murine colorectal cancer model and patient-derived colorectal cancer organoid.
RESULTS: We first demonstrated that within the tumor microenvironment, CD8+ TTST cells are highly susceptible to platinum-based chemotherapy, whereas CD8+ TBYS cells constitute a quiescent, chemo-resistant population. Leveraging this, CD8+ TBYS-targeted OV-BYTE therapy synergized with chemotherapy to control tumorigenesis in multiple murine models. Mechanistically, this dual combination directly engaged the CD8+ TBYS cell reservoir for tumor killing, which was accompanied by the restoration of CD8+ TTST cell function via reduced apoptotic susceptibility and acquisition of a polyfunctional, effector-like state. Consequently, integrating OV-BYTE into the standard chemo-PD-1 ICB regimen resulted in improved antitumor efficacy in both preclinical and patient-derived tumor models.
CONCLUSIONS: Our study establishes the chemotherapy-resistant CD8+ TBYS cell niche as a pivotal therapeutic target. By engaging this target, OV-BYTE emerges as a potent combinatorial agent that successfully circumvents a core limitation of standard chemo-immunotherapy, thus offering a rationally designed and translatable strategy to advance combination cancer therapy.