Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis

Abstract

The intrinsic role of endogenous IL-17A in spontaneous intestinal tumorigenesis has not been addressed previously to our knowledge. Ablation of IL-17A significantly reduced tumor development in mice bearing a heterozygote mutation in the adenomatous polyposis coli (APC) gene (Apc Min/+ mice). There was also a decrease in inflammatory cytokines and proinflammatory mediators, reduced infiltration of lymphocytes including T cells, and preservation of intestinal architecture and the presence of APC protein in intestinal epithelial cells. Interestingly, IL-17A ablation also corrected immunological abnormalities such as splenomegaly and thymic atrophy in Apc Min/+ mice. CD4 T cells from Apc Min/+ mice showed hyperproliferative potential in vitro and in vivo and increased levels of IL-17A and IL-10. The effector CD4 T cells from Apc Min/+ mice were more resistant to regulatory T cell-mediated suppression. Finally, these CD4 T cells induced colitis in immunodeficient mice upon adoptive transfer, whereas the ablation of IL-17A in CD4 T cells in Apc Min/+ mice completely abolished this pathogenic potential in vivo. Taken together, our results show that CD4 T cellderived IL-17A promotes spontaneous intestinal tumorigenesis with altered functions of CD4 T cells in Apc Min/+ mice.inflammation | T cells | colon cancer

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…Il17a deficiency reduces intestinal tumorigenesis in both colitis-associated and spontaneous intestinal cancer mouse models. 127,128 The loss of IL-23 signaling, which is critical for the generation of pathogenic Th17 responses, inhibits tumor growth in a spontaneous colon cancer mouse model; this finding is in agreement with the phenotype of Il17a-deficient mice. 129 As a consequence of the genetic lesions of colorectal cancer, either the early or late stage of colorectal tumors exhibit defects in their epithelial barrier integrity.…”

Murine CD27 (−) Vγ6 (+) γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

“…For example, the adoptive transfer of IL-17-producing CD4 (+) (Th17) cells has been shown to promote either tumor development or tumor regression (58)(59)(60). And IL-17(R) deficiency/blockade was associated with both enhanced (61) and reduced (23,(62)(63)(64) tumor load. The reasons for the highly variable anti-versus protumor activities of IL-17 and IL-17-producing T cells in distinct tumor models remain unclear and deserve further investigation.…”

A role for T-bet-mediated tumour immune surveillance in anti-IL-17A treatment of lung cancer

“…Although Th17 cells have been shown to promote cytotoxic T cell responses in a model of melanoma metastasis 24 , IL-17A has been found to favour tumour development in other models [25][26][27] . In fact, it has been previously reported that IL-17A boosts tumour development by inducing a tumour-promoting microenvironment 25 and that targeted deletion of IL-17A suppresses intestinal tumourigenesis 26 .…”

“…In fact, it has been previously reported that IL-17A boosts tumour development by inducing a tumour-promoting microenvironment 25 and that targeted deletion of IL-17A suppresses intestinal tumourigenesis 26 . Consistent with a pro-tumour function of IL-17A, it has also been reported that IL-17A expression is regulated by STAT3, a protooncogene activated by IL-6 in tumour and tumour stromal cells, promoting tumour cell survival, proliferation and angiogenesis 28,29 .…”