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Cell. 2018 Oct 4;175(2):429-441.e16. doi: 10.1016/j.cell.2018.08.061. Epub 2018 Sep 20.

LC3-Associated Phagocytosis in Myeloid Cells Promotes Tumor Immune Tolerance.

Author information

1
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
3
Department of Immunobiology, University of Arizona, Tucson, AZ 85724, USA; BIO5 Institute, University of Arizona, Tucson, AZ 85719, USA; Valley Fever Center for Excellence, University of Arizona, Tucson, AZ 85724, USA.
4
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
5
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
6
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
7
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: douglas.green@stjude.org.

Abstract

Targeting autophagy in cancer cells and in the tumor microenvironment are current goals of cancer therapy. However, components of canonical autophagy play roles in other biological processes, adding complexity to this goal. One such alternative function of autophagy proteins is LC3-associated phagocytosis (LAP), which functions in phagosome maturation and subsequent signaling events. Here, we show that impairment of LAP in the myeloid compartment, rather than canonical autophagy, induces control of tumor growth by tumor-associated macrophages (TAM) upon phagocytosis of dying tumor cells. Single-cell RNA sequencing (RNA-seq) analysis revealed that defects in LAP induce pro-inflammatory gene expression and trigger STING-mediated type I interferon responses in TAM. We found that the anti-tumor effects of LAP impairment require tumor-infiltrating T cells, dependent upon STING and the type I interferon response. Therefore, autophagy proteins in the myeloid cells of the tumor microenvironment contribute to immune suppression of T lymphocytes by effecting LAP.

KEYWORDS:

LC3-associated phagocytosis; STING; anti-cancer immunity; autophagy; efferocytosis; immune tolerance; macrophage polarization; tumor microenvironment; tumor-associated macrophages; type I interferon

PMID:
30245008
PMCID:
PMC6201245
[Available on 2019-10-04]
DOI:
10.1016/j.cell.2018.08.061
[Indexed for MEDLINE]

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