title: TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance.
abstract: Phagocytosis of apoptotic cells by myeloid cells has been implicated in the maintenance of immune homeostasis. In this study, we found that T cell immunoglobulin- and mucin domain-containing molecule-4 (TIM-4) repressed tumor-specific immunity triggered by chemotherapy-induced tumor cell death. TIM-4 was found to be highly expressed on tumor-associated myeloid cells such as macrophages (TAMs) and dendritic cells (TADCs) and danger-associated molecular patterns (DAMPs) released from chemotherapy-damaged tumor cells induced TIM-4 on tumor-associated myeloid cells recruited from bone marrow-derived precursors. TIM-4 directly interacted with AMPKα1 and activated autophagy-mediated degradation of ingested tumors, leading to reduced antigen presentation and impaired CTL responses. Consistently, blockade of the TIM-4-AMPKα1-autophagy pathway augmented the antitumor effect of chemotherapeutics by enhancing tumor-specific CTL responses. Our finding provides insight into the immune tolerance mediated by phagocytosis of dying cells, and targeting of the TIM-4-AMPKα1 interaction constitutes a unique strategy for augmenting antitumor immunity and improving cancer chemotherapy.
authors: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan.
authors: Muhammad
authors: M
authors: Baghdadi
authors: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan.
authors: Akihiro
authors: A
authors: Yoneda
authors: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan.
authors: Tsunaki
authors: T
authors: Yamashina
authors: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan.
authors: Hiroko
authors: H
authors: Nagao
authors: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.
authors: Yoshihiro
authors: Y
authors: Komohara
authors: Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan.
authors: Shigenori
authors: S
authors: Nagai
authors: Department of Immunology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan.
authors: Hisaya
authors: H
authors: Akiba
authors: INSERM, U1016, Institut Cochin, Paris, 75014, France; CNRS, UMR8104, Paris, 75014, France; Université Paris Descartes, Sorbonne Paris Cité, 75014, France.
authors: Marc
authors: M
authors: Foretz
authors: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan.
authors: Hironori
authors: H
authors: Yoshiyama
authors: Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, 060-0815, Japan.
authors: Ichiro
authors: I
authors: Kinoshita
authors: Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, 060-0815, Japan.
authors: Hirotoshi
authors: H
authors: Dosaka-Akita
authors: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.
authors: Motohiro
authors: M
authors: Takeya
authors: INSERM, U1016, Institut Cochin, Paris, 75014, France; CNRS, UMR8104, Paris, 75014, France; Université Paris Descartes, Sorbonne Paris Cité, 75014, France.
authors: Benoit
authors: B
authors: Viollet
authors: Department of Immunology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan.
authors: Hideo
authors: H
authors: Yagita
authors: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan. Electronic address: jinushi@igm.hokudai.ac.jp.
authors: Masahisa
authors: M
authors: Jinushi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001343:Autophagy / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D007108:Immune Tolerance / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000503:physiopathology; D014407:Tumor Cells, Cultured
chemical_list: D008565:Membrane Proteins; C500399:TIM-4 protein, mouse; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases