{
  "abstract": "Background Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have transformed cancer treatment across multiple malignancies, yielding durable responses in some patients. However, primary and acquired drug resistance limit their broader efficacy. Elucidating the underlying mechanisms and identifying strategies to overcome resistance require robust and clinically relevant preclinical models. Resistance to PD-1 blockade has been associated with several mechanisms: (1) impaired tumor antigen presentation, (2) downregulation of MHC class I molecules, (3) dysregulation of IFN-γ signaling pathways, and (4) establishment of an immunosuppressive tumor microenvironment. These factors collectively contribute to the escape of immune surveillance and treatment failure.Methods GemPharmatech has established three models of anti-PD-1 resistance. (1) Drug induced model: BALB/c-hPD1 mice were subcutaneously transplanted with CT26 cells and treated with anti-PD-1 (KEYTRUDA®) twice weekly. Non-responsive tumors were excised, dissociated, cultured, and then re-implanted into naïve mice for anti-PD-1 treatment to maintain drug pressure. The induced model of anti-PD-1 resistance was obtained after repeated transplantation cycles. (2) Genetically engineered model: Engineered anti-PD-1 resistant models were established by knocking out either B2m or Stk11 in CT26 cells, which are known to confer specific genetic alterations leading to anti-PD-1 resistance. (3) Primary resistance model.Results The drug-induced model demonstrated a significantly faster tumor growth kinetics in vivo compared to parental CT26. RNA sequencing revealed differential gene expression in resistant tumors, providing insight into the resistance mechanisms. In the engineered PD-1-resistant CT26 model, knocking out Stk11 dampened CT26’s response to anti-PD-1 treatment. Notably, CD8+ cytotoxic T lymphocyte infiltration decreased, and myeloid-derived suppressor cells (MDSCs) significantly accumulated in the tumor microenvironment. Additionally, Stk11 deletion was associated with reduced PD-L1 expression in tumor cells, suggesting that the immunosuppressive microenvironment contributed to the development of resistance.Conclusions These preclinical anti-PD-1 resistance models are valuable tools to dissect the complexity of anti-PD-1 resistance mechanisms, validate resistance-associated biomarkers and evaluate novel immunotherapeutic strategies.",
  "authors": [
    {
      "affiliations": [
        "GemPharmatech Co., Ltd., Nanjing, China"
      ],
      "name": "Yan Wang"
    },
    {
      "affiliations": [
        "GemPharmatech, Nanjing, China"
      ],
      "name": "Hongyan Sun"
    },
    {
      "affiliations": [
        "GemPharmatech Co., Ltd., Nanjing, China"
      ],
      "name": "Jianming Xu"
    },
    {
      "affiliations": [
        "GemPharmatech Co., Ltd., Nanjing, China"
      ],
      "name": "Xiang Gao"
    }
  ],
  "title": "780 Development of preclinical anti-PD-1 resistant models to uncover mechanisms of immune evasion",
  "uid": "9db992d3-811a-55b7-bb44-a3dba86b59ce"
}