Mitophagy in Gut Epithelial Cells Promotes Antitumor Immunity

High levels of cytotoxic CD8⁺ tumor-infiltrating lymphocytes (TIL) are associated with better prognosis for patients with colorectal cancer. Recent studies have shown that STAT3, which is known to mediate the suppression of antitumor immunity via multiple mechanisms, is overexpressed in colorectal cancer. To elucidate the mechanisms underlying elevated TIL levels in colorectal cancer, Ziegler and colleagues generated mice exhibiting intestinal epithelial cell (IEC)–specific ablation of Stat3. Treatment of Stat3^ΔIEC mice with the colon cancer–inducing mutagen azoxymethane (AOM) blocked AOM-induced tumorigenesis and resulted in increased levels of CD8⁺ T cells in preneoplastic colonic lesions. Similarly, IEC-specific loss of Stat3 promoted an adaptive immune response to delay tumorigenesis and prolong survival of a mouse model of constitutively activated Ctnnb (Ctnnb^ca)–driven colon tumorigenesis; further, high CD8⁺ T-cell levels and IFNγ were critical for increased survival. Increased lysosomal membrane permeabilization (LMP) was observed in STAT3-deficient IECs, and treatment of Ctnnb^ca;Stat3^ΔIEC mice with a chemical that induces LMP resulted in increased CD8⁺ T-cell levels. Ex vivo coculture experiments showed that LMP-mediated protease release was critical for antigen-specific T-cell activation via dendritic cell cross-dressing–driven MHC class I antigen presentation. STAT3-deficient mouse colon cancer cells and IECs exhibited increased lysosomal Fe²⁺ levels and elevated mitophagy, and STAT3-deficient cells exhibited improved oxidative phosphorylation compared with STAT3 wild-type cells; moreover, inhibition of mitophagy reduced Ifng expression. Treatment with an iron chelator resulted in the prevention of LMP in STAT3-deficient IECs in vitro and decreased survival of Ctnnb^ca;Stat3^ΔIEC mice. Consistent with these findings, the level of activated STAT3 was inversely correlated to that of CD8⁺ TILs in human colorectal cancer. These findings identify a cellular mechanism underlying increased levels of TILs in colorectal cancer and suggest a therapeutic strategy for enhancing antitumor immune responses in patients with colorectal cancer.

Ziegler PK, Bollrath J, Pallangyo CK, Matsutani T, Canli Ö, De Oliveria T, et al. Mitophagy in intestinal epithelial cells triggers adaptive immunity during tumorigenesis. Cell 2018 June 14 [Epub ahead of print].

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