ATG16L1 in myeloid cells limits colorectal tumor growth in mice infected with colibactin-producing via decreasing inflammasome activation.

strains producing the genotoxin colibactin, designated as CoPEC (colibactin-producing ), have emerged as an important player in the etiology of colorectal cancer (CRC). Here, we investigated the role of macroautophagy/autophagy in myeloid cells, an important component of the tumor microenvironment, in the tumorigenesis of a susceptible mouse model infected with CoPEC. For that, a preclinical mouse model of CRC, the mice, with deficiency specifically in myeloid cells (/) and the corresponding control mice (), were infected with a clinical CoPEC strain 11G5 or its isogenic mutant 11G5 that does not produce colibactin. We showed that myeloid cell-specific deficiency led to an increase in the volume of colonic tumors in mice under infection with 11G5, but not with 11G5. This was accompanied by increased colonocyte proliferation, enhanced inflammasome activation and IL1B/IL-1β secretion, increased neutrophil number and decreased total T cell and cytotoxic CD8 T cell numbers in the colonic mucosa and tumors. In bone marrow-derived macrophages (BMDMs), compared to uninfected and 11G5∆-infected conditions, 11G5 infection increased inflammasome activation and IL1B secretion, and this was further enhanced by autophagy deficiency. These data indicate that ATG16L1 in myeloid cells was necessary to inhibit colonic tumor growth in CoPEC-infected mice inhibiting colibactin-induced inflammasome activation and modulating immune cell response in the tumor microenvironment. : AOM, azoxymethane; APC, APC regulator of WNT signaling pathway; ATG, autophagy related; mice, mice deficient for specifically in myeloid cells; CASP1, caspase 1; BMDM, bone marrow-derived macrophage; CFU, colony-forming unit; CoPEC, colibactin-producing ; CRC, colorectal cancer; CXCL1/KC, C-X-C motif chemokine ligand 1; ELISA, enzyme-linked immunosorbent assay; IL, interleukin; MC, myeloid cell; MOI, multiplicity of infection; PBS, phosphate-buffered saline; , polyketide synthase; qRT-PCR, quantitative real-time reverse-transcription polymerase chain reaction; siRNA, small interfering RNA; TME, tumor microenvironment; TNF/TNF-α, tumor necrosis factor.