IL-36γ-armed oncolytic virus exerts superior efficacy through induction of potent adaptive antitumor immunity

• Published in: Cancer Immunology, Immunotherapy Vol. 70; no. 9; pp. 2467 - 2481
• Main Authors: Yang, Min, Giehl, Esther, Feng, Chao, Feist, Mathilde, Chen, Hongqi, Dai, Enyong, Liu, Zuqiang, Ma, Congrong, Ravindranathan, Roshni, Bartlett, David L., Lu, Binfeng, Guo, Zong Sheng
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2021; Springer Nature B.V
• Subjects: Adaptive Immunity; Animal models; Animals; Antitumor activity; Cancer; Cancer immunotherapy; Cancer Research; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell differentiation; Cell Line, Tumor; Cells, Cultured; Cytotoxicity, Immunologic; Dendritic cells; Disease Models, Animal; Effector cells; Gene Expression; Genetic Engineering; Genetic Therapy; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Humans; Immunology; Immunotherapy; Interleukin-1 - genetics; Lymphocytes T; Macrophages; Medicine; Medicine & Public Health; Melanoma, Experimental; Metastases; Mice; Molecular Imaging; Neoplasms - diagnosis; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - therapy; Oncology; Oncolysis; Oncolytic Virotherapy - adverse effects; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Original; Original Article; Suppressor cells; Treatment Outcome; Tumor microenvironment; Vaccinia; Xenograft Model Antitumor Assays; Effector memory T cells; CD4; CD8; Immunotherapy; IL-36; Oncolytic virus; T cells; CD8+ T cells; IL-36γ; CD4+ T cells
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-021-02860-4

In this study, we aimed to apply the cytokine IL-36 γ to cancer immunotherapy by constructing new oncolytic vaccinia viruses (OV) expressing interleukin-36 γ (IL-36 γ -OVs), leveraging unique synergism between OV and IL-36 γ ’s ability to promote antitumor adaptive immunity and modulate tumor microenvironment (TME). IL-36 γ -OV had dramatic therapeutic efficacies in multiple murine tumor models, frequently leading to complete cancer eradication in large fractions of mice. Mechanistically, IL-36- γ -armed OV induced infiltration of lymphocytes and dendritic cells, decreased myeloid-derived suppressor cells and M2-like tumor-associated macrophages, and T cell differentiation into effector cells. Further study showed that IL-36 γ -OV increased the number of tumor antigen-specific CD4 + and CD8 + T cells and the therapeutic efficacy depended on both CD8 + and CD4 + T cells. These results demonstrate that these IL36 γ -armed OVs exert potent therapeutic efficacy mainly though antitumor immunity and they may hold great potential to advance treatment in human cancer patients.