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Reshaping the Immune Microenvironment by Oncolytic Herpes Simplex Virus in Murine Pancreatic Ductal Adenocarcinoma
Liming Zhang1, Wei Wang2, Ruikun Wang1
1State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300350, PR China; Key Laboratory of Microbial Functional Genomics of Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, PR China.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is the major type of pancreatic malignancy with very poor prognosis. Despite the promising results of immune checkpoint inhibitors (ICIs) in some solid tumors, immunotherapy is less effective for PDAC due to its immunosuppressive tumor microenvironment (TME). In this report, we established an immunocompetent syngeneic PDAC model and investigated the effect of oncolytic herpes simplex virus-1 (oHSV) on the composition of TME immune cells. The oHSV treatment significantly reduced tumor burden and prolonged the survival of tumor-bearing mice. Further, by single cell RNA sequencing (scRNA-seq) and multicolor fluorescence-activated cell sorting (FACS) analysis, we demonstrated that oHSV administration downregulated tumor-associated macrophages (TAMs), especially the anti-inflammatory macrophages, and increased the percentage of tumor-infiltrating lymphocytes, including activated cytotoxic CD8+ T cells and T helper (Th)1 cells. Besides, the combination of oHSV and immune checkpoint modulators extended the lifespan of the tumor-bearing mice. Overall, our data suggested that oHSV reshapes the TME of PDAC by boosting the immune activity and leads to improved responsiveness of PDAC to immunotherapy.
Insights
Oncolytic herpes simplex virus-1 (oHSV) effectively reduced pancreatic cancer growth and improved survival in mice. This immunotherapy approach reshapes the tumor microenvironment, enhancing anti-tumor immune responses and increasing sensitivity to immune checkpoint inhibitors.
Area of Science:
- Oncology
- Immunology
- Virology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes.
- The immunosuppressive tumor microenvironment (TME) limits the efficacy of current immunotherapies like immune checkpoint inhibitors (ICIs).
Purpose of the Study:
- To investigate the impact of oncolytic herpes simplex virus-1 (oHSV) on the PDAC TME and its potential to enhance immunotherapy.
- To evaluate oHSV's efficacy in reducing tumor burden and prolonging survival in a preclinical PDAC model.
Main Methods:
- Established an immunocompetent syngeneic PDAC mouse model.
- Administered oHSV and assessed tumor growth, survival rates, and TME composition.
- Utilized single-cell RNA sequencing (scRNA-seq) and multicolor fluorescence-activated cell sorting (FACS) for immune cell profiling.
Main Results:
- oHSV treatment significantly reduced tumor burden and improved survival in mice.
- oHSV downregulated tumor-associated macrophages (TAMs), particularly anti-inflammatory subtypes.
- Increased infiltration of activated cytotoxic CD8+ T cells and T helper 1 (Th1) cells was observed.
- Combination therapy of oHSV and ICIs further extended survival.
Conclusions:
- oHSV effectively reshapes the PDAC TME by reducing immunosuppressive cells and promoting anti-tumor immunity.
- oHSV enhances the responsiveness of PDAC to immune checkpoint modulators.
- oHSV represents a promising therapeutic strategy for pancreatic cancer.
