TY - JOUR
T1 - LC3-Associated Phagocytosis in Myeloid Cells Promotes Tumor Immune Tolerance
AU - Cunha, Larissa D.
AU - Yang, Mao
AU - Carter, Robert
AU - Guy, Clifford
AU - Harris, Lacie
AU - Crawford, Jeremy C.
AU - Quarato, Giovanni
AU - Boada-Romero, Emilio
AU - Kalkavan, Halime
AU - Johnson, Michael D.L.
AU - Natarajan, Sivaraman
AU - Turnis, Meghan E.
AU - Finkelstein, David
AU - Opferman, Joseph T.
AU - Gawad, Charles
AU - Green, Douglas R.
N1 - Funding Information:
The authors thank Patrick Fitzgerald, Richard Cross, and Greig Lennon (SJCRH) for technical assistance and Peer Karmaus, Paul Thomas, Ben Youngblood (SJCRH), Peter Murray (Max Planck Institute), and Jennifer Martinez (NIEHS) for thoughtful insights and discussions. We also thank Hartwell Center for RNA sequencing and the Center for In Vivo Imaging and Therapeutics (supported by SJCRH, NCI R50 CA211481, and NCI P30 CA021765) for preclinical imaging (SJCRH). This work was supported by grants from the NIH ( AI40646 ), a Distinguished Innovator award from the Lupus Research Alliance , and ALSAC . C.G. is supported by a Career Award for Medical Scientists from the Burroughs Wellcome Fund .
Funding Information:
The authors thank Patrick Fitzgerald, Richard Cross, and Greig Lennon (SJCRH) for technical assistance and Peer Karmaus, Paul Thomas, Ben Youngblood (SJCRH), Peter Murray (Max Planck Institute), and Jennifer Martinez (NIEHS) for thoughtful insights and discussions. We also thank Hartwell Center for RNA sequencing and the Center for In Vivo Imaging and Therapeutics (supported by SJCRH, NCI R50 CA211481, and NCI P30 CA021765) for preclinical imaging (SJCRH). This work was supported by grants from the NIH (AI40646), a Distinguished Innovator award from the Lupus Research Alliance, and ALSAC. C.G. is supported by a Career Award for Medical Scientists from the Burroughs Wellcome Fund.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/10/4
Y1 - 2018/10/4
N2 - 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.
AB - 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.
KW - LC3-associated phagocytosis
KW - STING
KW - anti-cancer immunity
KW - autophagy
KW - efferocytosis
KW - immune tolerance
KW - macrophage polarization
KW - tumor microenvironment
KW - tumor-associated macrophages
KW - type I interferon
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U2 - 10.1016/j.cell.2018.08.061
DO - 10.1016/j.cell.2018.08.061
M3 - Article
C2 - 30245008
AN - SCOPUS:85053424990
VL - 175
SP - 429-441.e16
JO - Cell
JF - Cell
SN - 0092-8674
IS - 2
ER -