Reshaping the Immune Microenvironment by Oncolytic Herpes Simplex Virus in Murine Pancreatic Ductal Adenocarcinoma.

Affiliation

Zhang L(1), Wang W(2), Wang R(1), Zhang N(3), Shang H(4), Bi Y(4), Chen D(4), Zhang C(1), Li L(5), Yin J(5), Zhang H(6), Cao Y(7).
Author information:
(1)State 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.
(2)Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, PR China.
(3)Key Laboratory of Microbial Functional Genomics of Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, PR China.
(4)State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300350, PR China.
(5)Department of Immunology, Tianjin Medical University, Tianjin 300070, PR China; Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Tianjin 300070, PR China.
(6)State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300350, PR China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, PR China. Electronic address: [Email]
(7)State 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. Electronic address: [Email]

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.