Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8 + T Cell-Mediated Immunity in Colorectal Cancer

Abstract

Summary Although all-trans retinoic acid (atRA) is a key regulator of intestinal immunity, its role in colorectal cancer (CRC) is unknown. We found that mice with colitis-associated CRC had a marked deficiency in colonic atRA due to alterations in atRA metabolism mediated by microbiota-induced intestinal inflammation. Human ulcerative colitis (UC), UC-associated CRC, and sporadic CRC specimens have similar alterations in atRA metabolic enzymes, consistent with reduced colonic atRA. Inhibition of atRA signaling promoted tumorigenesis whereas atRA supplementation reduced tumor burden. The benefit of atRA treatment was mediated by cytotoxic CD8+ T cells, activated due to MHCI upregulation on tumor cells. Consistent with these findings, increased colonic expression of the atRA-catabolizing enzyme, CYP26A1, correlated with reduced frequencies of tumoral cytotoxic CD8+ T cells and with worse disease prognosis in human CRC. These results reveal a mechanism by which microbiota drive colon carcinogenesis and highlight atRA metabolism as a therapeutic target for CRC.

Novel insights into microbiome in colitis and colorectal cancer

“…In human sporadic CRC, UC and UC-associated CRC, the atRNA-synthesizing enzyme ALDH1 is significantly decreased whereas the atRNA-catabolizing enzyme CYP26A1 is increased, suggestive of common atRA deficiency in these pathologies (31*). Using the AOM/DSS CAC mouse model, Bhattacharya et al demonstrated that atRA protects against tumorigenesis by enhancing anti-tumor CD8+ T cell response and that microbiota-induced inflammatory cytokines promote differential expression of ALDH1 and CYP26A1 as observed in patients (31*). The microbiota metabolite butyrate was recently shown to stimulate ALDH1 expression, thereby increasing atRA levels in epithelial cells (32).…”

Permissive/Protective Interplay of Microbiota with T Cell Adaptive Immune Response in Colon Cancer

“…Researchers finally illustrated that pretreatment with broad-spectrum antibiotics, which deplete the whole microbiota, completely prevents all-trans-retinoic acids in this mouse model. Interestingly, human colon cancer specimens have also shown deficiency in all-trans-retinoic acid, similar to the animal model (46). Nevertheless, further investigation is required to determine if this deficiency in human colon cancer is related to microbiome and whether it can be reversed by all-trans-retinoic acid supplementation towards a better immune response and prognosis.…”

“…Depletion of all gut microorganisms by broad-spectrum antibiotics in animal models predisposed to colon cancer is another example of experiments, analyzing the association between whole microbiota and colon cancer. In general, antibiotic treatment of mice significantly decreases tumor formation and progression (46,47). There are studies on colon cancer linking a single bacterium, e.g.…”

“…As the study of human colon cancer samples has confirmed, Th1 adaptive immunity and presence of tumorspecific cytotoxic CD8+ cells are associated with better clinical outcomes and less tumor recurrence (55,56). On the other hand, experimental animal models have presented firm evidence indicating the influence of microbiota on tumor-specific CD8+ T cell responses (46). Additionally, Bhattacharya et al investigated the mentioned association in a mouse model of colon cancer with deficiency in colonic all-trans-retinoic acid.…”

“…The authors showed that all-trans-retinoic acid supplementation could reduce the tumor burden in these mice. According to the findings, the advantage of all-trans-retinoic acid treatment was mediated by cytotoxic CD8+ T cells, which were activated due to major histocompatibility complex class-I upregulation (CD8 ligands) by all-trans-retinoic acid on tumor cells (46). Consistent with the abovementioned findings, increased colonic expression of all-trans-retinoic-acidcatabolizing enzyme, CYP26A1, was found to be correlated with the reduced frequency of tumoral cytotoxic CD8+ T cells and poor disease prognosis.…”