Microbiota-induced S100A11-RAGE axis underlies immune evasion in right-sided colon adenomas and is a therapeutic target to boost anti-PD1 efficacy.

BACKGROUND: Tumourigenesis in right-sided and left-sided colons demonstrated distinct features. OBJECTIVE: We aimed to characterise the differences between the left-sided and right-sided adenomas (ADs) representing the early stage of colonic tumourigenesis. DESIGN: Single-cell and spatial transcriptomic datasets were analysed to reveal alterations between right-sided and left-sided colon ADs. Cells, animal experiments and clinical specimens were used to verify the results. RESULTS: Single-cell analysis revealed that in right-sided ADs, there was a significant reduction of goblet cells, and these goblet cells were dysfunctional with attenuated mucin biosynthesis and defective antigen presentation. An impairment of the mucus barrier led to biofilm formation in crypts and subsequent bacteria invasion into right-sided ADs. The regions spatially surrounding the crypts with biofilm occupation underwent an inflammatory response by lipopolysaccharide (LPS) and an apoptosis process, as revealed by spatial transcriptomics. A distinct S100A11+ epithelial cell population in the right-sided ADs was identified, and its expression level was induced by bacterial LPS and peptidoglycan. S100A11 expression facilitated tumour growth in syngeneic immunocompetent mice with increased myeloid-derived suppressor cells (MDSC) but reduced cytotoxic CD8+ T cells. Targeting S100A11 with well-tolerated antagonists of its receptor for advanced glycation end product (RAGE) (Azeliragon) significantly impaired tumour growth and MDSC infiltration, thereby boosting the efficacy of anti-programmed cell death protein 1 therapy in colon cancer. CONCLUSION: Our findings unravelled that dysfunctional goblet cells and consequential bacterial translocation activated the S100A11-RAGE axis in right-sided colon ADs, which recruits MDSCs to promote immune evasion. Targeting this axis by Azeliragon improves the efficacy of immunotherapy in colon cancer.

Auricularia auricula-judae Attenuates the Progression of Metabolic Syndrome in High-Fat Diet-Induced Obese Rats: Enzymatic Pre-Digestion Technology Is Superior to Superfine Grinding Method.

Auricularia auricula-judae (AAJ) has been cultivated for food in China for centuries, and is also used as a folk medicine for the regulation of glucose and lipid metabolism. However, there are few studies on the effects of different processing technologies on the therapeutic efficacy of AAJ to date. This study investigated the effectiveness of the AAJ made by using superfine grinding and enzymatic pre-digestion technologies, respectively, in a high-fat diet obese rat model. It was found that oral administrations of two AAJ products significantly alleviated dyslipidemia by decreasing serum lipid levels and restoring liver functions. AAJ products made by using pre-digestion technology have appreciable potential to ameliorate lipid metabolic disorders over other products, possibly due to the higher levels of dietary fiber, crude polysaccharides, and total flavonoids released from AAJ during processing. By analysis of transcriptome sequencing and protein expression, it was clear that starch and sucrose metabolism and glycerolipid metabolism-related factors involved in fatty acid synthesis and metabolism in the liver of obese rats were significantly improved. This study gives further evidence that AAJ significantly ameliorates the progression of glucose and lipid metabolism in obese rats. Moreover, this study demonstrated for the first time that the pre-digestion method may be a better and more efficient processing approach for the improvement of AAJ bioavailability.

Pharmacologic inhibition of IL11/STAT3 signaling increases MHC-I expression and T cell infiltration.

BACKGROUND: Recent studies have discovered an emerging role of IL11 in various colitis-associated cancers, suggesting that IL11 mainly promotes tumor cell survival and proliferation in regulating tumorigenesis. Herein we aimed to reveal a novel function of IL-11 through STAT3 signaling in regulating tumor immune evasion. METHODS: AOM/DSS model in Il11-/- and Apcmin/+/Il11-/- mice were used to detect tumor growth and CD8+ T infiltration. STAT1/3 phosphorylation and MHC-I, CXCL9, H2-K1 and H2-D1 expression were detected in MC38 cells and intestine organoids treated with/without recombinant IL11 to explore effect of IL11/STAT3 signaling, with IL11 mutein used to competitively inhibit IL11 and rescue inhibited STAT1 activation. Correlation between IL11 and CD8+ T infiltration was analyzed using TIMER2.0 website. IL11 expression and survival prognosis was analyzed in clinical data of patient cohort from Nanfang Hospital. RESULTS: IL11 is highly expressed in CRC and indicates unfavorable prognosis. IL11 knockout increased CD8+ T cell infiltration and reduced intestinal and colon formation. Tumors were significantly suppressed while MHC-I and CXCL9 expression for CD8+ T infiltration were remarkably increased in the tumor tissues of Apcmin/+/Il11-/- mice or Il11-/- mice induced by AOM/DSS. IL11/STAT3 signaling downregulated MHC-I and CXCL9 by inhibiting IFNγ-induced STAT1 phosphorylation. IL11 mutein competitively inhibit IL11 to upregulate CXCL9 and MHC-I in tumor and attenuated tumor growth. CONCLUSIONS: This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.