Enhanced gut barrier integrity sensitizes colon cancer to immune therapy

Abstract

Oral IL-10 suppressed tumor growth in the APCmin/+ mouse/Bacteroides fragilis colon cancer model while a similar formulation of IL-12 exacerbated disease. In contrast, combined treatment with IL-10 and IL-12 resulted in near-complete tumor eradication and a significant extension of survival. The cytokines mediated distinct immunological effects in the gut, i.e. IL-10 diminished Th17 cell prevalence whereas IL-12 induced IFNγ and enhanced CD8 + T-cell activity. Loss-of-function studies demonstrated that IL-12-driven CD8 + T-cell expansion was only partially responsible for the synergy, and that both the detrimental and the beneficial activities of IL-12 required IFNγ. Examination of colon physiology in mice receiving single vs dual treatment revealed that exacerbation of disease by IL-12 monotherapy was associated with compromised gut barrier integrity whereas combined treatment reversed this effect, uncovering additional activity by the cytokines on the stroma. Further analysis showed that the stromal effects of IL-12 included a 6-fold increase in IL-10RA expression in the colon epithelium, linking the epithelial activity of the cytokines. Finally, dual but not monotherapy induced a 3-fold increase in tight junction protein levels in the colon, identifying the mechanism by which IL-10 blocked the detrimental effect of the IL-12-IFNγ axis on barrier function without interfering with its beneficial immunological activity. These findings establish that the synergy between IL-12 and IL-10 was mediated by pleiotropic effects on the immune and the non-immune compartments and that the latter activity was critical to therapeutic outcome.

Role of Gut Microbiota in the Anti‐Colitic Effects of Anthocyanin‐Containing Potatoes

“…[ 49 ] Altered intestinal permeability has been linked to IBD as well as colon cancer. [ 50 ] The integrity of the mucus layer and tight junction are two critical points to maintain intestinal epithelial barrier function. [ 7 ] The mucus layer provides the first physiochemical defense to protect the epithelium, which makes the secretion of mucins more critical.…”

The Role of Immune Response and Microbiota on Campylobacteriosis

“…Only a single layer of IEC separates nearly sterile internal intestinal tissue from microbe-rich intestinal lumen, hence the integrity of IEC is essential for intestinal health. Notably, IEC line breakdown is often implicated in various intestinal disorders such as IBD [16], irritable bowel syndrome (IBS) [17], colorectal cancer [18], and C. difficile infection [19]. The destruction of IEC line and tissue upon invasion of C. jejuni [20] clearly demonstrates the important role of the epithelial cells.…”

Emerging Complexity in CD4+T Lineage Programming and Its Implications in Colorectal Cancer

“…Mouse models indicate IL-10 can actually augment cancer responses. Indeed, exogenous IL-10 is being investigated as a therapeutic option in multiple cancer types, including CRC ( 166 , 167 ). Identification of the specific cellular sources of IL-10 that inhibit tumor immunity and targeted suppression of IL-10 production in those cells, or inhibition of IL-10RA signaling in tumor cells, may offer improved safety and efficacy.…”

“…When administered to mice harboring a toxigenic strain of B. fragilis , IL-12 monotherapy leads to increased tumor CTL numbers, though no change in tumor burden was seen. Co-administration of IL-10 also reduces tumor Th17 numbers, and dramatically improves tumor burden ( 167 ). This cooperative effect is promising, and suggests additional interactions could be similarly exploited.…”