LC3-Associated Phagocytosis in Myeloid Cells Promotes Tumor Immune Tolerance

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / immunology
  • Cell Line
  • Host-Pathogen Interactions
  • Humans
  • Immune Tolerance / immunology
  • Immune Tolerance / physiology*
  • Macrophages
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / metabolism
  • Microtubule-Associated Proteins / physiology*
  • Myeloid Cells / metabolism
  • Phagocytosis / physiology*
  • Phagosomes / physiology
  • T-Lymphocytes / metabolism
  • Tumor Microenvironment / physiology

Substances

  • Microtubule-Associated Proteins
  • light chain 3, human