IL-36γ Transforms the Tumor Microenvironment and Promotes Type 1 Lymphocyte-Mediated Antitumor Immune Responses

Xuefeng Wang; Xin Zhao; Chao Feng; Aliyah Weinstein; Rui Xia; Wen Wen; Quansheng Lv; Shuting Zuo; Peijun Tang; Xi Yang; Xiaojuan Chen; Hongrui Wang; Shayang Zang; Lindsay Stollings; Timothy L Denning; Jingting Jiang; Jie Fan; Guangbo Zhang; Xueguang Zhang; Yibei Zhu; Walter Storkus; Binfeng Lu

doi:10.1016/j.ccell.2015.07.014

IL-36γ Transforms the Tumor Microenvironment and Promotes Type 1 Lymphocyte-Mediated Antitumor Immune Responses

Cancer Cell. 2015 Sep 14;28(3):296-306. doi: 10.1016/j.ccell.2015.07.014. Epub 2015 Aug 27.

Authors

Xuefeng Wang¹, Xin Zhao², Chao Feng³, Aliyah Weinstein⁴, Rui Xia⁵, Wen Wen³, Quansheng Lv³, Shuting Zuo⁶, Peijun Tang⁷, Xi Yang⁸, Xiaojuan Chen⁹, Hongrui Wang¹⁰, Shayang Zang⁵, Lindsay Stollings¹¹, Timothy L Denning¹², Jingting Jiang¹³, Jie Fan¹⁴, Guangbo Zhang¹⁵, Xueguang Zhang³, Yibei Zhu³, Walter Storkus⁴, Binfeng Lu¹⁶

Affiliations

¹ Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China; Department of Immunology, Institute of Medical Biotechnology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China.
² Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
³ Department of Immunology, Institute of Medical Biotechnology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China.
⁴ Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Department of Dermatology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
⁵ Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Department of Immunology, Institute of Medical Biotechnology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China.
⁶ Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Department of Surgery, The Second Hospital of Jilin University, Changchun 130041, China.
⁷ Department of Pulmonary Tuberculosis, The Affiliated Hospital for Infectious Diseases of Soochow University, Suzhou 215007, China.
⁸ Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA; School of Medicine, Tsinghua University, Peking 100084, China.
⁹ Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA; Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
¹⁰ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
¹¹ Department of Anesthesiology, University of Pittsburgh Medical Center, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA.
¹² Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.
¹³ Department of Tumor Biotherapy, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China.
¹⁴ Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh PA 15240, USA.
¹⁵ Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
¹⁶ Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA. Electronic address: binfeng@pitt.edu.

Abstract

Cytokines play a pivotal role in regulating tumor immunogenicity and antitumor immunity. IL-36γ is important for the IL-23/IL-17-dominated inflammation and anti-BCG Th1 immune responses. However, the impact of IL-36γ on tumor immunity is unknown. Here we found that IL-36γ stimulated CD8(+) T cells, NK cells, and γδ T cells synergistically with TCR signaling and/or IL-12. Importantly, IL-36γ exerted profound antitumor effects in vivo and transformed the tumor microenvironment in favor of tumor eradication. Furthermore, IL-36γ strongly increased the efficacy of tumor vaccination. Moreover, IL-36γ expression inversely correlated with the progression of human melanoma and lung cancer. Our study establishes a role of IL-36γ in promoting antitumor immune responses and suggests its potential clinical translation into cancer immunotherapy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Neoplasm / immunology
CD8-Positive T-Lymphocytes / immunology*
Cancer Vaccines / immunology
Humans
Immunotherapy / methods
Interleukin-1 / immunology*
Interleukin-12 / immunology
Killer Cells, Natural / immunology*
Lung Neoplasms / immunology
Melanoma, Experimental / immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Receptors, Antigen, T-Cell, gamma-delta / immunology
Tumor Cells, Cultured
Tumor Microenvironment / immunology*

Substances

Antigens, Neoplasm
Cancer Vaccines
IL36G protein, human
Interleukin-1
Receptors, Antigen, T-Cell, gamma-delta
Interleukin-12

Abstract

Publication types

MeSH terms

Substances

Grants and funding