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
  • 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: [email protected].
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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