Noncanonical Autophagy in Myeloid Cells Drives Tumor Immune Tolerance

Canonical ATG-driven autophagy, which results in the degradation of cellular components by the formation of autolysosomes, paradoxically inhibits the outgrowth of malignant cells during early tumorigenesis and promotes tumor progression during the later stages of tumorigenesis. Recently, LC3-associated phagocytosis (LAP) was identified as an autophagosome-independent noncanonical autophagy pathway in phagocytic cells such as macrophages. Given that LAP defects in macrophages were shown to result in the elevation of proinflammatory cytokines, Cunha and colleagues sought to ascertain the effects of myeloid LAP in the tumor microenvironment. Loss of LAP, but not canonical autophagy, in macrophages suppressed syngeneic and autochthonous tumor growth and was shown to drive M1 polarization of tumor-associated macrophages (TAM). Further, single-cell RNA sequencing revealed that loss of LAP in TAMs resulted in impaired phagocytosis of dying tumor cells and induced a type I interferon response. Ablation of type I interferon signaling restored tumor growth in mice with LAP-deficient macrophages. Similarly, transfection of DNA to activate stimulator of interferon genes (STING), which drives type I interferon production in non-phagocytosing cells, resulted in expression of type I interferon in LAP-deficient macrophages, and ablation of STING restored tumor growth in mice with LAP-deficient macrophages. Ablation of LAP in macrophages resulted in increased CD4⁺ and CD8⁺ tumor-infiltrating lymphocyte (TIL)–mediated type I interferon production and effector function, and depletion of interferonγ or either CD4⁺ or CD8⁺ T cells resulted in reduced tumor growth in LAP-deficient mice. Taken together, these findings provide further insight into the role of noncanonical autophagy in myeloid antitumor immune response and suggest that inhibition of LAP may promote the repolarization of immunosuppressive TAMs.

Cunha LD, Yang M, Carter R, Guy C, Harris L, Crawford JC, et al. LC3-associated phagocytosis in myeloid cells promotes tumor immune tolerance. Cell 2018175:429–41.e16.

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