LC3-Associated Phagocytosis in Myeloid Cells Promotes Tumor Immune Tolerance

Larissa D. Cunha, Mao Yang, Robert Carter, Clifford Guy, Lacie Harris, Jeremy C. Crawford, Giovanni Quarato, Emilio Boada-Romero, Halime Kalkavan, Michael D.L. Johnson, Sivaraman Natarajan, Meghan E. Turnis, David Finkelstein, Joseph T. Opferman, Charles Gawad, Douglas R. Green

Research output: Contribution to journalArticle

59 Scopus citations

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. Impairment of LC3-associated phagocytosis in myeloid cells of the tumor microenvironment has anti-tumor effects.

Original languageEnglish (US)
Pages (from-to)429-441.e16
JournalCell
Volume175
Issue number2
DOIs
StatePublished - Oct 4 2018

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Cunha, L. D., Yang, M., Carter, R., Guy, C., Harris, L., Crawford, J. C., Quarato, G., Boada-Romero, E., Kalkavan, H., Johnson, M. D. L., Natarajan, S., Turnis, M. E., Finkelstein, D., Opferman, J. T., Gawad, C., & Green, D. R. (2018). LC3-Associated Phagocytosis in Myeloid Cells Promotes Tumor Immune Tolerance. Cell, 175(2), 429-441.e16. https://doi.org/10.1016/j.cell.2018.08.061