{
  "abstract": "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.",
  "authors": [
    {
      "affiliations": [
        "Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Yang Yang"
    },
    {
      "affiliations": [
        "Institute of Immunology, Third Military Medical University, Chongqing, China"
      ],
      "name": "Junjian He"
    },
    {
      "affiliations": [
        "Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Texi Liang"
    },
    {
      "affiliations": [
        "Institute for Immunology and Pathogenesis, College of Basic Medicine, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Kaiyi Li"
    },
    {
      "affiliations": [
        "Department of Urology, South China Hospital of Shenzhen University, Shenzhen, Guangdong, China"
      ],
      "name": "Yao Lin"
    },
    {
      "affiliations": [
        "Institute of Immunology, Third Military Medical University, Chongqing, China"
      ],
      "name": "Hairu Wang"
    },
    {
      "affiliations": [
        "Institute of Immunology, Third Military Medical University, Chongqing, China"
      ],
      "name": "Wenwen Xi"
    },
    {
      "affiliations": [
        "Institute for Immunology and Pathogenesis, College of Basic Medicine, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Shusen Ye"
    },
    {
      "affiliations": [
        "Institute for Immunology and Pathogenesis, College of Basic Medicine, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Ding Qiu"
    },
    {
      "affiliations": [
        "Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Chunyang Xie"
    },
    {
      "affiliations": [
        "Institute of Immunology, Third Military Medical University, Chongqing, China"
      ],
      "name": "Yaxing Hao"
    },
    {
      "affiliations": [
        "Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China"
      ],
      "name": "Teming Li"
    },
    {
      "affiliations": [
        "Cancer Center, Daping Hospital and Army Medical Center of PLA, Third Military Medical University, Chongqing, China"
      ],
      "name": "Shuai Yue"
    },
    {
      "affiliations": [
        "Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China",
        "Institute of Immunology, Third Military Medical University, Chongqing, China"
      ],
      "name": "Lilin Ye"
    },
    {
      "affiliations": [
        "Department of Rheumatology and Immunology, Center for Immune Ageing and Rejuvenation, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China"
      ],
      "name": "Xiangyu Chen"
    }
  ],
  "title": "Oncolytic virotherapy potentiates chemo-PD-1 immunotherapy by engaging chemo-resistant bystander CD8+ T cells",
  "uid": "d5e13b94-9418-5c07-bc61-627518ee8e7e"
}