The DNA Methylcytosine Dioxygenase Tet2 Sustains Immunosuppressive Function of Tumor-Infiltrating Myeloid Cells to Promote Melanoma Progression

Wen Pan, Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale Cancer Center, Yale Cooperative Center of Excellence in Hematology, Yale University, New Haven, CT 06520, USA.
Shu Zhu, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Institute of Immunology, University of Science and Technology of China, Hefei 230027, China; CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
Kun Qu, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
Katrina Meeth, Department of Pathology, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06519, USA.
Jijun Cheng, Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale Cancer Center, Yale Cooperative Center of Excellence in Hematology, Yale University, New Haven, CT 06520, USA.
Kaixin He, Institute of Immunology, University of Science and Technology of China, Hefei 230027, China; CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
Hongdi Ma, Institute of Immunology, University of Science and Technology of China, Hefei 230027, China; CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
Yan Liao, Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou 510060, China.
Xizhi Wen, Biotherapy Center, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Christine Roden, Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale Cancer Center, Yale Cooperative Center of Excellence in Hematology, Yale University, New Haven, CT 06520, USA.
Zuzana Tobiasova, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Zheng Wei, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Jun Zhao, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Jun Liu, Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale Cancer Center, Yale Cooperative Center of Excellence in Hematology, Yale University, New Haven, CT 06520, USA.
Ji Zheng, Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale Cancer Center, Yale Cooperative Center of Excellence in Hematology, Yale University, New Haven, CT 06520, USA; Department of Urology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Bo Guo, Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; General Hospital of People's Liberation Army, Beijing, China.
Sajid A. Khan, Department of Surgery, Yale University School of Medicine, New Haven, CT 06519, USA.Follow
Marcus Bosenberg, Department of Pathology, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06519, USA.Follow
Richard A. Flavell, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.Follow
Jun Lu, Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale Cancer Center, Yale Cooperative Center of Excellence in Hematology, Yale University, New Haven, CT 06520, USA. Electronic address: jun.lu@yale.edu.Follow

Document Type

Article

Publication Title

Immunity

Abstract

Ten-Eleven-Translocation-2 (Tet2) is a DNA methylcytosine dioxygenase that functions as a tumor suppressor in hematopoietic malignancies. We examined the role of Tet2 in tumor-tissue myeloid cells and found that Tet2 sustains the immunosuppressive function of these cells. We found that Tet2 expression is increased in intratumoral myeloid cells both in mouse models of melanoma and in melanoma patients and that this increased expression is dependent on an IL-1R-MyD88 pathway. Ablation of Tet2 in myeloid cells suppressed melanoma growth in vivo and shifted the immunosuppressive gene expression program in tumor-associated macrophages to a proinflammatory one, with a concomitant reduction of the immunosuppressive function. This resulted in increased numbers of effector T cells in the tumor, and T cell depletion abolished the reduced tumor growth observed upon myeloid-specific deletion of Tet2. Our findings reveal a non-cell-intrinsic, tumor-promoting function for Tet2 and suggest that Tet2 may present a therapeutic target for the treatment of non-hematologic malignancies.

First Page

284

Last Page

297.e5

DOI

10.1016/j.immuni.2017.07.020

Publication Date

8-15-2017

Identifier

28813659 (pubmed); NIHMS898100 (mid); PMC5710009 (pmc); 10.1016/j.immuni.2017.07.020 (doi); S1074-7613(17)30327-8 (pii)

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