Journal
IMMUNITY
Volume 39, Issue 6, Pages 1070-1081Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2013.09.014
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Ministry of Health, Labour and Welfare
- Grants-in-Aid for Scientific Research [23501283, 24790479, 23591132, 23590534, 25112701, 25461503, 25293089, 23130501] Funding Source: KAKEN
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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 AMPK alpha 1 and activated autophagy-mediated degradation of ingested tumors, leading to reduced antigen presentation and impaired CTL responses. Consistently, blockade of the TIM-4-AMPK alpha 1-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-AMPK alpha 1 interaction constitutes a unique strategy for augmenting antitumor immunity and improving cancer chemotherapy.
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