2. Academic Validation
  3. TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance

TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance

  • Immunity. 2013 Dec 12;39(6):1070-81. doi: 10.1016/j.immuni.2013.09.014.
Muhammad Baghdadi 1,  Akihiro Yoneda 1,  Tsunaki Yamashina 1,  Hiroko Nagao 1,  Yoshihiro Komohara 2,  Shigenori Nagai 3,  Hisaya Akiba 4,  Marc Foretz 5,  Hironori Yoshiyama 1,  Ichiro Kinoshita 6,  Hirotoshi Dosaka-Akita 6,  Motohiro Takeya 2,  Benoit Viollet 5,  Hideo Yagita 4,  Masahisa Jinushi 7
Affiliations

Affiliations

  • 1 Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan.
  • 2 Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.
  • 3 Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan.
  • 4 Department of Immunology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan.
  • 5 INSERM, U1016, Institut Cochin, Paris, 75014, France; CNRS, UMR8104, Paris, 75014, France; Université Paris Descartes, Sorbonne Paris Cité, 75014, France.
  • 6 Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, 060-0815, Japan.
  • 7 Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan. Electronic address: jinushi@igm.hokudai.ac.jp.
PMID: 24315994 DOI: 10.1016/j.immuni.2013.09.014
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.

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