Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth

Abstract

Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of β-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses1,2. Curiously, however, ‘inflammatory signature’ genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer3,4. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates5, referred to as ‘tumour elicited inflammation’6. Although infiltrating CD4+ TH1 cells and CD8+ cytotoxic T cells constitute a positive prognostic sign in colorectal cancer7,8, myeloid cells and T-helper interleukin (IL)-17-producing (TH17) cells promote tumorigenesis5,6, and a ‘TH17 expression signature’ in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival9. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier10. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.

New insights into IL-12-mediated tumor suppression

“…142,143 In colorectal carcinoma, the effects of IL-23 were mimicked after blocking IL-17A. 144 In DMBA/ TPA-induced skin papillomas and MCA-induced fibrosarcomas, the protumorigenic effects of IL-23 were independent of the main Th17 cytokine. 145 In contrast to the protumoral role of endogenous IL-23, the administration of this cytokine by different delivery methods induced potent antitumor responses.…”

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

“…13 , 22 In contrast, intratumoral production of the cytokines IL23 and TNFα did not depend on MyD88 expression in our hands, and TH17 transcripts were also essentially independent of Myd88, compared to earlier studies. 13 , 23 These discrepancies may be at least in part explained by the different genetic mouse models used, and by the differences in tumor differentiation stages varying between carcinoma and adenoma. However, differences in gut microbiota and their derived TLR-ligands, which obviously occur between different animal facilities, cannot be excluded.…”

Enhanced gut barrier integrity sensitizes colon cancer to immune therapy

“…Consistent with this paradigm, a significant body of literature supports a major role for microbially-driven type 17 T-cell immunity (including Th17 and γδT-cell subsets) in colon cancer. 7–10 Importantly, analysis of clinical CRC samples has revealed an inverse relationship in CD8+ cytotoxic T-lymphocyte (CTL)/Th17 cell ratio between MMR-deficient (high CTL, low Th17) and ICI-resistant MMR-proficient (low CTL, high Th17) tumors; 11 supporting the notion that the outcome of immune therapy in CRC may be dependent on the ability to alter the CTL – Th17 cell balance.…”

“…However, once dysplasia develops, it will result in local compromise of the barrier and lead to what has been termed “tumor-elicited inflammation,” a process that in turn promotes the growth of established adenomas. 7 Therefore, chronic inflammation is tightly intertwined both with tumorigenesis and tumor progression in the colon. Consistent with this paradigm, a significant body of literature supports a major role for microbially-driven type 17 T-cell immunity (including Th17 and γδT-cell subsets) in colon cancer.…”