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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. Introduction Colorectal cancer (CRC) is the second leading cause of cancer mortality in the U.S. (), and ulcerative colitis (UC), a chronic inflammatory condition of the colon, has been shown to predispose individuals to CRC ().

Despite advances in therapy, however, 20–30% of UC patients still undergo colectomy because they are refractory to current therapy or because they have developed CRC. Unfortunately, surgery is often associated with significant postoperative morbidities (). Thus, there remains an urgent need for improved therapy and effective chemoprophylaxis in UC and UC-associated cancer. The vitamin A metabolite all- trans retinoic acid (atRA) is required for several crucial physiological processes (;; ). In recent years, atRA has been shown to regulate both the innate and adaptive immune systems and, in particular, to play a requisite role in shaping intestinal immunity (; ). AtRA maintains immune homeostasis in the intestinal lamina propria mainly by potentiating the induction and maintenance of regulatory T-cells and reciprocally inhibiting the development of Th17 cells (;;; ). Additionally, in certain pathological settings, atRA can also elicit proinflammatory effector T-cell responses (;;; ).

However, despite the critical influence of atRA on intestinal immunity, its role in CRC has not been previously investigated. We hypothesized that a local deficiency of atRA might promote the development of CRC, especially in the context of intestinal inflammation. Therefore, we studied atRA metabolism in colitis-associated CRC. Our findings reveal a link between microbiota-induced intestinal inflammation, atRA deficiency, and CRC in mice and humans, as well as a strong anti-tumor effect of atRA mediated through CD8 + effector T-cells. Mice with colitis-associated cancer are deficient in colonic atRA due to altered atRA metabolism To investigate the role of atRA metabolism in CRC development, we used a mouse model that recapitulates progression from colitis to cancer: the AOM-DSS model (). In this model, the colonotropic carcinogen azoxymethane (AOM) is combined with the inflammatory agent dextran sodium sulfate (DSS) to induce chronic intestinal inflammation and tumor formation in the distal colons of mice within nine to ten weeks, with dysplasia appearing as early as week three.

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In contrast, mice administered DSS alone develop chronic colitis without tumorigenesis (). In line with our hypothesis that a local deficiency of atRA might promote the development of CRC, colonic atRA levels, as measured by quantitative mass spectrometry, were significantly reduced in mice with colitis-associated cancer (CAC) as early as four weeks after AOM-DSS induction, when mice had chronic inflammation with dysplastic changes in the colon. AtRA levels further declined to approximately half the normal colonic atRA level by week nine, when carcinomas became apparent ( and ). To investigate whether this deficiency could result from altered expression of atRA metabolic enzymes, we analyzed the colonic expression of key enzymes that function in the synthesis of atRA—the retinaldehyde dehydrogenases, ALDH1A1, ALDH1A2, and ALDH1A3—and the catabolism of atRA—the cytochrome p450 (CYP) family members, CYP26A1, CYP26B1, and CYP26C1—during progression from colitis to cancer.

Because ALDH1A1 is the most abundantly expressed ALDH1A isoform in the normal mouse colon (data not shown), and CYP26A1 is the most catalytically active of the three CYP26 enzymes (), we focused our analyses on these enzymes. Colonic ALDH1A1 protein expression declined in mice with chronic colitis and in mice with CAC throughout disease progression, ultimately decreasing by 50–70% compared to age-matched normal mice ( and ). This reduction was also observed at the transcript level (). ALDH1A2 protein expression remained unchanged (), whereas ALDH1A3 was consistently decreased during disease progression ().

AOM-DSS mice have a deficiency in colonic atRA that can be attributed to alterations in atRA metabolism In contrast to the atRA synthesis enzymes, the colonic transcript levels of the atRA catabolizing enzyme CYP26A1 were increased four-fold in mice with chronic colitis (), and three-to eight-fold (depending on the CYP26 isoform) in mice with CAC. Upregulation was observed as early as one week after AOM-DSS induction, with levels declining thereafter ( and ).

We next sought to partition out the contribution of various cell types to the colonic atRA deficiency. Although Aldh1a1 expression was reduced in colonic epithelial cells, T-cells, and macrophages or dendritic cells in CAC mice (), Cyp26a1 expression was increased only in the epithelial compartment (). Given the relative abundance of epithelial cells compared to immune cells () and the observation that epithelial cells exhibit alterations in both Aldh1a1 and Cyp26a1, the atRA deficiency observed in colitis or CAC can largely be attributed to the epithelial cells. Taken together, these findings indicate that mice with CAC have a marked decrease in colonic atRA as a result of a decrease in the atRA-synthesizing ALDH1A enzymes and an increase in the atRA-catabolizing CYP26 enzymes. Abnormal atRA metabolism is a common feature of ulcerative colitis and colorectal cancer in humans To assess whether atRA deficiency is present in UC-associated CRC, we examined the expression of ALDH1A1 and CYP26A1 in colonic resections from UC and UC-associated CRC patients. In specimens from UC patients, there was a significant decrease in ALDH1A1 and a corresponding increase in CYP26A1 in colitis regions compared to matched uninvolved regions of tissue () and in dysplastic tissue compared to matched colitis tissue ().

ALDH1A1 and CYP26A1 were also lower and higher, respectively, in colon adenocarcinomas compared to matched normal regions (). Using a tissue microarray, we found that the same ALDH1A1 and CYP26A1 differential expression was conserved in sporadic adenocarcinomas compared to normal colons and adenomas (). Transcript expression of ALDH1A1 was also decreased and CYP26A1 increased in colon cancer specimens from an independent microarray dataset, GSE39582 () (). Inflammation triggered by intestinal microbiota induces atRA enzyme alteration in mice with CAC To investigate whether atRA deficiency can exacerbate CRC tumorigenesis, we treated mice with the pan-retinoic acid receptor (RAR) inverse agonist BMS493 () four weeks prior to and throughout disease progression following AOM-DSS induction. This treatment led to a significant increase in tumor burden (), compelling us to investigate the mechanism responsible for the atRA enzyme deregulation observed in mice with CAC. Several investigators have demonstrated the pro-tumorigenic effects of intestinal microbiota in CRC (;; ), with broad-spectrum antibiotics dramatically reducing tumor incidence in animal models of CRC, including the AOM-DSS model (; ). We therefore hypothesized that bacterial influx into the colon, due to defective barrier permeability, could induce colonic atRA enzyme alteration in the context of colitis and CRC.

In accord with our hypothesis, pretreatment with broad-spectrum antibiotics completely prevented both the decrease in Aldh1a1 and increase in Cyp26a1 in mice with CAC ( and ). Antibiotic-treated AOM-DSS mice also exhibited significantly increased body weights and dramatically reduced tumor burdens compared to untreated AOM-DSS mice (). Inflammation triggered by intestinal microbiota induces atRA enzyme alteration in AOM-DSS mice Having demonstrated that atRA enzymes are altered not only in CAC but also during chronic colitis (), we hypothesized that inflammation driven by gut microbiota could contribute to the altered enzyme expression. In line with our hypothesis, the colons of antibiotic-treated AOM-DSS mice not only had healthier colitis scores compared to untreated AOM-DSS mice ( and ), but also showed a striking reduction in the expression of several proinflammatory cytokines (TNFα, IFNγ, IL-1β, IL-17A, IL-12, IL-6 and IL-23) (). To test whether these proinflammatory cytokines could be altering atRA enzymes in colitis or CAC, we asked whether culturing epithelial organoids with these cytokines, or whether injecting these cytokines into the mucosal wall of the distal colon of antibiotic-treated mice (), could alter the expression of Aldh1a1 and Cyp26a1. In both contexts, the proinflammatory cytokines induced a significant decrease in Aldh1a1 and increase in Cyp26a1 (). Next, we investigated the cell types responsible for secreting the various proinflammatory cytokines in the colons of mice with CAC.

The myeloid compartment secreted a wide range of these cytokines, including TNFα, IL-1β, IL-6 and IL-12, while the epithelial cells secreted TNFα and T-cells secreted IL-17A ( and ). Antibiotic treatment not only markedly reduced cytokine secretion from all these cell types, but also substantially reduced immune cell infiltration into the colon ( and ). These results show that expression of the atRA metabolic enzymes is altered by inflammatory cytokines released from colonic epithelial cells and infiltrating immune cells in response to the influx of gut microbiota across a defective mucosal barrier. AtRA supplementation decreases tumor burden in mice with CAC Given the altered atRA metabolism in AOM-DSS mice as well as in human CRC, we assessed whether treatment with atRA could decrease tumor burden. We used two distinct methods for this purpose: 1) intraperitoneal injection of atRA and 2) oral administration of Liarozole, an inhibitor of the CYP26 enzymes that catabolize atRA ().

Liarozole’s ability to increase available endogenous atRA was demonstrated in vitro using RARE-luciferase assays () on two colon cancer cell lines, MC38 and CT26, and in vivo via mass spectrometry of colons of AOM-DSS mice orally gavaged with Liarozole (). AtRA was administered to AOM-DSS mice either starting early, when acute colitis was established, or later, after dysplastic changes had occurred in the colon. In both cases, tumor burden in atRA-treated mice was reduced by more than half compared to vehicle-treated mice (). Consistent with atRA treatment, Liarozole treatment also resulted in a 50% reduction in tumor burden ().

These data demonstrate a robust therapeutic benefit conferred by atRA supplementation. AtRA treatment elicits a pronounced CD8 + T-cell response in mice with CAC Next, we sought to identify the mechanism responsible for the anti-tumor effect of atRA. Since CD8 + T-cells play a crucial role in anti-tumor immunity, we examined the CD8 + T-cell response in AOM-DSS mice treated with atRA. A significant increase in the percentage of CD8 + T-cells expressing the early activation marker CD69 was seen in tumors and MLNs in atRA-treated mice ( and ). The atRA-mediated increase in activated CD8 + T-cells was more pronounced in the lamina propria (LP) than the intra-epithelial lymphocyte (IEL) layer of the tumor ().

In addition, the percentage of proliferating intratumoral CD8 + T-cells nearly doubled in atRA-treated mice (). Thus, a robust CD8 + T-cell response is induced by atRA treatment of mice with CAC. The anti-tumor effect of atRA is CD8 + T-cell dependent To determine the functional relevance of the CD8 + T-cell response elicited by atRA treatment, we evaluated the therapeutic benefit of atRA in AOM-DSS mice depleted of CD8 + T-cells () as well as in CD8-deficient ( Cd8a −/−) mice. AtRA had no effect on tumor burden in either CD8 + T-cell-depleted mice or Cd8a −/− mice (), demonstrating that the therapeutic effect of atRA is dependent on CD8 + T-cells. Consistent with this idea, we observed a four-fold increase in tumor cell death in atRA-treated AOM-DSS mice compared to vehicle-treated mice (), with CD8 + T-cells in close proximity to TUNEL + tumor cells in the atRA-treated condition (). This increase in tumor cell death was completely abrogated in CD8 + T-cell-depleted mice (). Importantly, the therapeutic benefit of atRA treatment in Cd8a −/− mice was restored upon adoptive transfer of CD8 + T-cells ( and ).

Although mature CD4 + T-cells can be reprogrammed in an atRA-dependent manner into MHCII-restricted CD8αα + IELs with cytotoxic functions (; ), in the context of CAC, atRA treatment did not increase the frequency of this cell type (). These results therefore demonstrate that the therapeutic benefit conferred by atRA is dependent on CD8 + T-cells. A detailed analysis of CD4 + T-cells did not reveal any significant changes in the number () or activation status of these cells in the tumors and MLNs of atRA-treated mice (). Moreover, CD4 + T-cells isolated from the tumor or surrounding tissue from atRA-treated mice did not show any differences in TNFα, IFNγ, or IL-17A secretion compared to vehicle-treated mice (). Interestingly, there was a significant increase in the frequency of CD4 +FOXP3 + regulatory T (Treg) cells in tumors of atRA-treated mice (); however, this increase in tumoral Treg cells was observed in atRA-treated Cd8a −/− mice as well (), which are refractory to the therapeutic benefit of atRA, indicating that the anti-tumor effect of atRA is not mediated through Treg cells alone.

In a study in mice with DSS-induced colitis, atRA supplementation suppressed colitis by inducing γδ + T-cells to secrete IL-22 (). However, in our studies, atRA treatment of Tcrd −/− mice still significantly decreased tumor burden, indicating that γδ + T-cells are not required for the anti-tumor effect of atRA (). Nonetheless, we observed that the colonic tissue surrounding the tumoral regions in atRA-treated mice had reduced inflammation scores, which could contribute to the atRA-mediated reduction in tumor burden in parallel with the CD8 + T-cell mechanism ().

AtRA upregulates MHCI expression on tumor epithelial cells to promote T-cell cytotoxicity Given that CD8 + T-cells are the dominant mediator of the anti-tumor effect of atRA, we sought to determine the mechanistic basis of the CD8 + T-cell-dependent effect of atRA treatment on CAC. Since CD8 + T-cell-mediated cytotoxicity is MHC class I-restricted, we analyzed the expression of MHCI on the tumor epithelial cells before and after atRA treatment and found that mice treated with atRA exhibited a significant increase in MHCI ( and ). Interestingly, this atRA-mediated increase in MHCI was abrogated when the retinoic acid receptor alpha (RARα) was deleted from intestinal epithelial cells using Vil1-cre- Rara fl/fl mice (). In line with the direct mode of action of atRA on tumor epithelial cells, exogenous addition of atRA to the human colon cancer cell line Caco-2 in vitro also increased MHCI expression ().

AtRA upregulates MHCI expression on tumor epithelial cells, leading to increased cytotoxic T lymphocytes Next, we considered the possibility that increased MHCI expression on tumor epithelial cells could render them more susceptible to CD8 + cytotoxic-T-cell killing. Indeed, Vil1-cre- Rara fl/fl mice that lack the atRA-mediated upregulation of MHCI were resistant to the anti-tumor effects of atRA (). Consistent with this, intratumoral CD8 + T-cells in atRA-treated AOM-DSS wild-type mice expressed higher levels of granzyme B, indicating increased cytotoxic activity ( and ), which was not seen in Vil1-cre- Rara fl/fl mice (). Consequently, untreated Vil1-cre- Rara fl/fl mice induced with AOM-DSS had a trend toward a higher tumor burden than control mice (). To determine if atRA acted on epithelial cells, and not myeloid cells or CD8 + T-cells, to mediate its anti-tumor effects, we tested whether mice lacking RARα expression in macrophages ( Lyz2-cre- Rara fl/fl mice), dendritic cells ( Itgax-cre- Rara fl/fl mice) and CD8 + T-cells (through adoptive transfer of CD8 + T-cells from Cd4-cre- Rara fl/fl mice into Cd8a −/− mice, as CD8 + T-cells in these mice lack the receptor due to cre expression in the double-positive thymocytes) were responsive to the anti-tumor effects of atRA. Importantly, all of the aforementioned mice exhibited lower tumor burdens upon atRA treatment, confirming that the anti-tumor effect of atRA was not dependent on direct effects of atRA on these cell types ().

These results demonstrate that atRA acts directly on tumor epithelial cells to upregulate MHCI, thereby rendering them sensitive to CD8 + T-cell-mediated killing. To assess our findings in another model of CRC, we investigated whether the MC38 subcutaneous tumor model was similarly responsive to atRA through a CD8 + T-cell-mediated mechanism. In line with our observations from the AOM-DSS model, we found that, while wild-type mice subcutaneously implanted with MC38 were responsive to the anti-tumor effect of atRA, Cd8a −/− mice were not (). Moreover, atRA-treated MC38 tumor mice had a significantly higher expression of MHCI on their tumor cells compared to vehicle-treated mice ().

CYP26A1 in colon carcinoma correlates with reduced cytotoxic CD8 + T-cell frequency and worse disease prognosis The findings from our mouse studies suggest that intestinal atRA deficiency dampens the CD8 + T-cell-mediated anti-tumor responses, which is known to correlate with overall survival in CRC (;; ). We therefore correlated ALDH1A1 and CYP26A1 expression in each core biopsy from the sporadic colon cancer tissue microarray with tumoral CD8 + T-cell density and granzyme B expression to determine if atRA metabolism could predict cytotoxic T-cell potential. Fotografia Per Principianti Pdf Merge here. Indeed, there was a significant negative correlation between CYP26A1 expression and both tumoral CD8 + T-cell density () and percentage of CD8 + T-cells expressing granzyme B in CRC specimens ().

We found no significant correlation with ALDH1A1 (data not shown). We also tested whether ALDH1A1 and CYP26A1 mRNA expression correlates with disease prognosis using the GSE39582 dataset (). This dataset has a large number of CRC samples obtained from a multi-center cohort (n=566) containing information on overall survival and disease-free survival.

Although ALDH1A1 expression did not correlate with disease prognosis, CYP26A1 expression correlated inversely with both overall survival and disease-free survival (). Discussion atRA has shown promise in the treatment of several malignancies.

In acute promyelocytic leukemia, it is known to act by inducing post-maturation apoptosis of the leukemic cells (). Despite its established regulatory role in intestinal immunity, the influence of atRA on CRC development has not been previously examined.

Our findings reveal that mice with CAC have significantly reduced levels of atRA in their colons due to a marked decrease in atRA-synthesizing ALDH1A enzymes and an increase in atRA-catabolizing CYP26 enzymes, imputing an important role to atRA in CRC. Direct evidence of the adverse effect of an atRA deficit was demonstrated in mice with CAC.

In these mice, further inhibition of atRA signaling increased tumor burden, while, conversely, atRA supplementation reduced tumor burden. Interestingly, depletion of the intestinal microbiota in AOM-DSS mice prevented the alteration of the atRA enzymes. The absence of intestinal bacteria in germ-free mice and antibiotic-treated mice has been demonstrated to dramatically reduce tumor formation in several models of CRC (; ). Increased inflammation and production of genotoxic metabolites are among the mechanisms by which microbiota potentiate colon carcinogenesis (; ). However, our study demonstrates yet another mechanism by which intestinal microbiota may promote CRC—by altering atRA metabolism.

An important finding of our study is that CRC patients have similar alterations in atRA metabolism in their tumors irrespective of whether they had a history of colitis. High inter-patient variability in our tissue microarray analysis of ALDH1A1 and CYP26A1 in sporadic colon carcinomas and adenomas may reflect differences in the extent of barrier permeability or associated inflammation. Similarly, adenocarcinomas may exhibit lower expression of epithelial tight junction proteins and greater barrier permeability compared to adenomas, possibly explaining the more pronounced enzyme changes in carcinomas (; ).

Nevertheless, when compared with normal colonic mucosa, colitis, dysplasia and colon carcinoma are all characterized by a decrease in ALDH1A1 and a concomitant increase in the CYP26A1, indicative of reduced colonic levels of atRA. These findings are in accord with recent investigations of sporadic CRC (), including a study demonstrating that CYP26B1 expression directly correlates with disease prognosis (). In the present study, we found a significant correlation between CYP26A1 transcript expression and both overall survival and disease-free survival in a multi-center cohort of CRC patients (). Our findings that abnormal atRA metabolism correlates with clinical prognosis and is present across most pre-neoplastic and neoplastic conditions of the colon, combined with the observed exacerbation of disease in mice with CAC upon inhibition of atRA signaling and the therapeutic benefit of atRA supplementation, suggest that atRA deficiency is an important factor in the pathogenesis of CRC. A number of possible mechanisms might explain the beneficial anti-tumor effect of atRA. In a mouse model of Crohn’s disease, atRA supplementation attenuated disease progression by promoting Treg cell-mediated intestinal tolerance ().

In another study, atRA supplementation ameliorated DSS-induced colitis, but through a mechanism that was γδ + T cell-dependent. However, in our studies, the anti-tumor effect of atRA was found to be independent of γδ + T-cells. Since in vitro studies have shown that atRA can induce apoptosis of colon cancer cell lines, albeit at high non-physiological concentrations (; ), we considered the possibility that the therapeutic benefit of atRA was due to a direct apoptotic effect on the tumor cells. In our studies, atRA treatment did lead to tumor cell apoptosis in vivo, but, surprisingly, the therapeutic effect of atRA was mediated by CD8 + T-cells rather than through a direct anti-tumor effect. Previous studies have shown that atRA can elicit CD4 + or CD8 + effector T-cell responses in the context of infection (; ). Here, in CAC, we found that atRA treatment led to an increase in tumoral CD8 + T-cell cytotoxic activity.

Furthermore, using Vil1-cre- Rara fl/fl mice we found that atRA treatment directly acts on tumor epithelial cells to upregulate MHCI expression, thereby rendering them more susceptible to killing by CD8 + cytotoxic T lymphocytes. Consistent with this mechanism, previous in vitro studies have demonstrated that MHCI is a direct transcriptional target of atRA (;; ). Untreated Vil1-cre- Rara fl/fl mice induced with AOM-DSS did not develop more tumors than control mice, but since mice with CAC already have dramatically reduced levels of atRA, the absence of RARα on epithelial cells likely would have had little impact on tumor burden. Our findings from the mouse model of CAC suggest that atRA deficiency in human CRC could impair effector cytotoxic T-cell function, resulting in accelerated growth of tumors. Consistent with this hypothesis, we found a strong negative correlation between abnormal atRA metabolism and both tumoral CD8 + T-cell frequency and granzyme B expression in human CRC.

Several studies have shown that infiltration of T-cells, especially CD8 + T-cells, as well as MHCI expression by tumor cells, correlates with improved CRC prognosis (;;; ). Our work not only provides a potential explanation for these phenomena, but also suggests that restoration of atRA levels in the colon could provide a therapeutic benefit in human CRC by promoting MHCI expression by tumor cells and cytotoxic T-cell function. Drug treatment 200μg BMS493 (Tocris Bioscience) or DMSO alone (vehicle) was i.p.

Injected into female C57BL/6 mice 4 weeks prior to induction with AOM-DSS and continued until the end of the AOM-DSS treatment period. 200μg atRA or DMSO alone (vehicle) was i.p.

Injected into AOM-DSS mice either twice a week or every other day. 80 ppm Liarozole (Tocris Bioscience) was incorporated into a base diet containing 4 IU/g of vitamin A (Research Diets). Mice were orally gavaged with 400μg Liarozole or polyethylene glycol-200 (vehicle) after induction with AOM-DSS daily until the end of week 4. Statistics Experimental data were analyzed with the Mann Whitney U-test using Prism (GraphPad Software), unless otherwise stated. Tissue microarray data were analyzed using the One-way ANOVA test, and correlation analysis was performed using the Pearson’s correlation test. Kaplan Meier curves for disease-free survival and overall survival were generated and analyzed with Prism (GraphPad software) using the Log-rank (Mantel Cox) test. Results are represented as mean ± SEM.

Author ContributionsN.B. Conceived the study, performed all experiments, and wrote the manuscript; T.R.P., H.X.L.P., N.R.F., J.A.K. Helped in designing the research and provided technical assistance. Provided pathology assistance.

Provided experimental help. Provided experimental assistance for the atRA mass spectrometry measurements. L.T., and O.C. Provided technical assistance with flow cytometry. Provided patient specimens for histology. Supervised the study and wrote the manuscript. All authors read and approved the final manuscript.

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