High fat stems tumor immune surveillance
Authors: Roberta Caruso, Grace Y. Chen
Journal: Cell Reports Medicine (2021)

In a recent issue of Cell Stem Cell, Beyaz et al. show that high-fat diets promote tumorigenesis by reducing major histocompatibility complex (MHC) class II expression in intestinal stem cells. Dietary modulation of epithelial MHC II expression is regulated by the gut microbiota. In a recent issue of Cell Stem Cell, Beyaz et al. show that high-fat diets promote tumorigenesis by reducing major histocompatibility complex (MHC) class II expression in intestinal stem cells. Dietary modulation of epithelial MHC II expression is regulated by the gut microbiota. Main textColorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related mortality worldwide. CRC has typically been a disease associated with increasing age, and heightened screening has resulted in a decline in CRC incidence in older individuals. However, there has been an alarming increase in early-onset colorectal cancers in individuals less than 50 years of age. Thus, there is a clear need to identify and mitigate risk factors, particularly lifestyle factors, that contribute to colorectal carcinogenesis.A hallmark of colorectal carcinogenesis is dysregulation of Wnt signaling and expansion of stem-like cells, marked by expression of Lgr5. Obesity and a high-fat diet (HFD) have been associated with increased risk for developing CRC, but the mechanism behind this association remains to be fully understood. Beyaz et al. had previously demonstrated that an HFD can drive Lgr5+ intestinal stem cell (ISC) proliferation and their capacity to self-renew via peroxisome proliferator-activated receptor-delta (PPAR-δ) signaling1Beyaz S. Mana M.D. Roper J. Kedrin D. Saadatpour A. Hong S.J. Bauer-Rowe K.E. Xifaras M.E. Akkad A. Arias E. et al.High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.Nature. 2016; 531: 53-58Crossref PubMed Scopus (391) Google Scholar. A HFD has also been associated with pathologic changes in the composition of the gut microbiota, known as dysbiosis, that can directly contribute to colorectal tumorigenesis2Yang J. Wei H. Zhou Y. Szeto C.H. Li C. Lin Y. Coker O.O. Lau H.C.H. Chan A.W.H. Sung J.J.Y. Yu J. High-Fat Diet Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites.Gastroenterology. 2021; (Published online August 27, 2021)https://doi.org/10.1053/j.gastro.2021.08.041Abstract Full Text Full Text PDF Scopus (35) Google Scholar. Recently, Beyaz et al.3Beyaz S. Chung C. Mou H. Bauer-Rowe K.E. Xifaras M.E. Ergin I. Dohnalova L. Biton M. Shekhar K. Eskiocak O. et al.Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis.Cell Stem Cell. 2021; 28: 1922-1935 e5Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar discovered a new mechanism linking diet and CRC risk via gut microbiota-mediated modulation of anti-tumor immunity.An essential step in immune surveillance is the presentation of tumor antigen via major histocompatibility complex (MHC) class I and MHC class II on the cell surface of antigen-presenting cells for recognition by CD8 and CD4 T cells, respectively, that lead to their activation. Although cytotoxic CD8 T cells have been considered the major players in immune surveillance, CD4 T cells also play a critical role in anti-tumor immunity via secretion of effector cytokines and promotion of CD8 cytotoxic T cell responses. Consistently, high MHC class II expression has been associated with better prognosis in CRC patients while loss of expression correlated with reduced tumor-infiltrating T cells and higher metastatic potential.4Sconocchia G. Eppenberger-Castori S. Zlobec I. Karamitopoulou E. Arriga R. Coppola A. Caratelli S. Spagnoli G.C. Lauro D. Lugli A. et al.HLA class II antigen expression in colorectal carcinoma tumors as a favorable prognostic marker.Neoplasia. 2014; 16: 31-42Crossref PubMed Scopus (72) Google Scholar,5Warabi M. Kitagawa M. Hirokawa K. Loss of MHC class II expression is associated with a decrease of tumor-infiltrating T cells and an increase of metastatic potential of colorectal cancer: immunohistological and histopathological analyses as compared with normal colonic mucosa and adenomas.Pathol. Res. Pract. 2000; 196: 807-815Crossref PubMed Scopus (30) Google Scholar In a kras-driven mouse model of intestinal cancer, a HFD altered the gut microbiome, which, in turn, resulted in reduced MHC class II expression on dendritic cells and increased tumorigenesis.6Schulz M.D. Atay C. Heringer J. Romrig F.K. Schwitalla S. Aydin B. Ziegler P.K. Varga J. Reindl W. Pommerenke C. et al.High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity.Nature. 2014; 514: 508-512Crossref PubMed Scopus (285) Google Scholar Beyaz et al. found that HFDs reduced MHC class II expression in intestinal epithelial cells, and in particular, in ISCs, that was independent of PPAR-δ signaling and obesity that was not diet-related.3Beyaz S. Chung C. Mou H. Bauer-Rowe K.E. Xifaras M.E. Ergin I. Dohnalova L. Biton M. Shekhar K. Eskiocak O. et al.Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis.Cell Stem Cell. 2021; 28: 1922-1935 e5Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Using an orthotopic mouse model of CRC in which Lgr5+ ISCs with loss of the tumor suppressor Apc are implanted into the colon, Beyaz et al. demonstrated that MHC class II-negative ISCs exhibited greater tumor-initiating capacity than their MHC class II-positive counterparts in HFD-fed mice. Furthermore, in mice that had loss of APC as well as MHC class II expression in Lgr5+ ISCs, larger tumors developed compared with mice that had intact MHC class II expression. MHC class II-related effects in Lgr5+ ISCs on tumorigenesis were not cell-intrinsic and did not involve stemness, as MHC class II-deficient APC-null Lgr5+ ISCs were still capable of forming tumor organoids in vitro and had similar organoid forming efficiencies to that of their MHC class II-expressing counterparts. Rather, the effects on tumorigenesis required the presence of B and T cells that mediate adaptive immunity. These findings by Beyaz et al. are exciting in that they suggest a role for ISC MHC class II-mediated immune surveillance in suppressing carcinogenesis that can be modulated by the diet.How MHC class II expression in ISCs is regulated is not entirely known; however, Beyaz et al. demonstrated that the gut microbiota plays a critical role. Numerous studies have highlighted the role of the gut microbiota in colorectal carcinogenesis. Specifically, several bacterial species, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and pks+ Escherichia coli are enriched in human CRC.7Yu A.I. Chen G.Y. The Gut Microbiome and Colorectal Cancer.in: Sun J. Inflammation, Infection, and Microbiome in Cancers. Springer, Cham, 2021: 63-96Crossref Google Scholar These oncomicrobes have been shown to promote tumorigenesis in preclinical models via several mechanisms including genotoxicity, dysregulation of Wnt signaling via β-catenin activation, and upregulation of pro-inflammatory signaling pathways.7Yu A.I. Chen G.Y. The Gut Microbiome and Colorectal Cancer.in: Sun J. Inflammation, Infection, and Microbiome in Cancers. Springer, Cham, 2021: 63-96Crossref Google Scholar In the study by Beyaz et al., a new mechanism was revealed, namely regulation of ISC MHC class II expression (Figure 1).3Beyaz S. Chung C. Mou H. Bauer-Rowe K.E. Xifaras M.E. Ergin I. Dohnalova L. Biton M. Shekhar K. Eskiocak O. et al.Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis.Cell Stem Cell. 2021; 28: 1922-1935 e5Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar In particular, Beyaz et al. showed that HFDs resulted in changes in the composition of the gut microbiota, including a significant decrease in the abundance of Helicobacter and Odoribacter spp. Co-housing and fecal transplantation studies using Helicobacter-positive and Helicobacter-negative donors confirmed the direct correlation between Helicobacter abundance and intestinal epithelial MHC class II expression levels. Future work involving monoassociation studies in gnotobiotic mice will be needed to further clarify the role of Helicobacter as well as other bacterial populations whose abundance is affected by HFDs in the regulation of ISC MHC class II expression, immune surveillance, and tumor susceptibility.To determine how the gut microbiota modulates MHC class II expression in ISCs, Beyaz et al. measured levels of innate immune receptors that are capable of sensing gut microbes and observed that a HFD diet reduced the expression of Toll-like receptor (Tlr) 2 and nucleotide-binding oligomerization domain (Nod) 2. In addition, HFD-fed mice exhibited reduced intestinal interferon-gamma (IFNγ) levels, and bulk RNA-seq of ISCs revealed downregulation of IFNγ-induced genes. Treatment of HFD-fed mice with a dual TLR2/NOD2 agonist or IFNγ increased MHC class II expression in ISCs. These findings are in line with previous evidence showing that the gut microbiota regulates the intestinal expression of TLR2 and NOD2, and that TLR-mediated expression of MHC class II requires IFNγ production by lamina propria lymphocytes.8Petnicki-Ocwieja T. Hrncir T. Liu Y.J. Biswas A. Hudcovic T. Tlaskalova-Hogenova H. Kobayashi K.S. Nod2 is required for the regulation of commensal microbiota in the intestine.Proc. Natl. Acad. Sci. USA. 2009; 106: 15813-15818Crossref PubMed Scopus (438) Google Scholar, 9Hörmann N. Brandão I. Jäckel S. Ens N. Lillich M. Walter U. Reinhardt C. Gut microbial colonization orchestrates TLR2 expression, signaling and epithelial proliferation in the small intestinal mucosa.PLoS ONE. 2014; 9: e113080Crossref PubMed Scopus (72) Google Scholar, 10Koyama M. Mukhopadhyay P. Schuster I.S. Henden A.S. Hulsdunker J. Varelias A. Vetizou M. Kuns R.D. Robb R.J. Zhan P. et al.MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota.Immunity. 2019; 51: 885-898 e7Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Altogether, these findings highlight the interplay between diet, the gut microbiota, and the host immune system on CRC susceptibility and support the incorporation of dietary strategies to promote anti-tumor immunity. Main textColorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related mortality worldwide. CRC has typically been a disease associated with increasing age, and heightened screening has resulted in a decline in CRC incidence in older individuals. However, there has been an alarming increase in early-onset colorectal cancers in individuals less than 50 years of age. Thus, there is a clear need to identify and mitigate risk factors, particularly lifestyle factors, that contribute to colorectal carcinogenesis.A hallmark of colorectal carcinogenesis is dysregulation of Wnt signaling and expansion of stem-like cells, marked by expression of Lgr5. Obesity and a high-fat diet (HFD) have been associated with increased risk for developing CRC, but the mechanism behind this association remains to be fully understood. Beyaz et al. had previously demonstrated that an HFD can drive Lgr5+ intestinal stem cell (ISC) proliferation and their capacity to self-renew via peroxisome proliferator-activated receptor-delta (PPAR-δ) signaling1Beyaz S. Mana M.D. Roper J. Kedrin D. Saadatpour A. Hong S.J. Bauer-Rowe K.E. Xifaras M.E. Akkad A. Arias E. et al.High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.Nature. 2016; 531: 53-58Crossref PubMed Scopus (391) Google Scholar. A HFD has also been associated with pathologic changes in the composition of the gut microbiota, known as dysbiosis, that can directly contribute to colorectal tumorigenesis2Yang J. Wei H. Zhou Y. Szeto C.H. Li C. Lin Y. Coker O.O. Lau H.C.H. Chan A.W.H. Sung J.J.Y. Yu J. High-Fat Diet Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites.Gastroenterology. 2021; (Published online August 27, 2021)https://doi.org/10.1053/j.gastro.2021.08.041Abstract Full Text Full Text PDF Scopus (35) Google Scholar. Recently, Beyaz et al.3Beyaz S. Chung C. Mou H. Bauer-Rowe K.E. Xifaras M.E. Ergin I. Dohnalova L. Biton M. Shekhar K. Eskiocak O. et al.Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis.Cell Stem Cell. 2021; 28: 1922-1935 e5Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar discovered a new mechanism linking diet and CRC risk via gut microbiota-mediated modulation of anti-tumor immunity.An essential step in immune surveillance is the presentation of tumor antigen via major histocompatibility complex (MHC) class I and MHC class II on the cell surface of antigen-presenting cells for recognition by CD8 and CD4 T cells, respectively, that lead to their activation. Although cytotoxic CD8 T cells have been considered the major players in immune surveillance, CD4 T cells also play a critical role in anti-tumor immunity via secretion of effector cytokines and promotion of CD8 cytotoxic T cell responses. Consistently, high MHC class II expression has been associated with better prognosis in CRC patients while loss of expression correlated with reduced tumor-infiltrating T cells and higher metastatic potential.4Sconocchia G. Eppenberger-Castori S. Zlobec I. Karamitopoulou E. Arriga R. Coppola A. Caratelli S. Spagnoli G.C. Lauro D. Lugli A. et al.HLA class II antigen expression in colorectal carcinoma tumors as a favorable prognostic marker.Neoplasia. 2014; 16: 31-42Crossref PubMed Scopus (72) Google Scholar,5Warabi M. Kitagawa M. Hirokawa K. Loss of MHC class II expression is associated with a decrease of tumor-infiltrating T cells and an increase of metastatic potential of colorectal cancer: immunohistological and histopathological analyses as compared with normal colonic mucosa and adenomas.Pathol. Res. Pract. 2000; 196: 807-815Crossref PubMed Scopus (30) Google Scholar In a kras-driven mouse model of intestinal cancer, a HFD altered the gut microbiome, which, in turn, resulted in reduced MHC class II expression on dendritic cells and increased tumorigenesis.6Schulz M.D. Atay C. Heringer J. Romrig F.K. Schwitalla S. Aydin B. Ziegler P.K. Varga J. Reindl W. Pommerenke C. et al.High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity.Nature. 2014; 514: 508-512Crossref PubMed Scopus (285) Google Scholar Beyaz et al. found that HFDs reduced MHC class II expression in intestinal epithelial cells, and in particular, in ISCs, that was independent of PPAR-δ signaling and obesity that was not diet-related.3Beyaz S. Chung C. Mou H. Bauer-Rowe K.E. Xifaras M.E. Ergin I. Dohnalova L. Biton M. Shekhar K. Eskiocak O. et al.Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis.Cell Stem Cell. 2021; 28: 1922-1935 e5Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Using an orthotopic mouse model of CRC in which Lgr5+ ISCs with loss of the tumor suppressor Apc are implanted into the colon, Beyaz et al. demonstrated that MHC class II-negative ISCs exhibited greater tumor-initiating capacity than their MHC class II-positive counterparts in HFD-fed mice. Furthermore, in mice that had loss of APC as well as MHC class II expression in Lgr5+ ISCs, larger tumors developed compared with mice that had intact MHC class II expression. MHC class II-related effects in Lgr5+ ISCs on tumorigenesis were not cell-intrinsic and did not involve stemness, as MHC class II-deficient APC-null Lgr5+ ISCs were still capable of forming tumor organoids in vitro and had similar organoid forming efficiencies to that of their MHC class II-expressing counterparts. Rather, the effects on tumorigenesis required the presence of B and T cells that mediate adaptive immunity. These findings by Beyaz et al. are exciting in that they suggest a role for ISC MHC class II-mediated immune surveillance in suppressing carcinogenesis that can be modulated by the diet.How MHC class II expression in ISCs is regulated is not entirely known; however, Beyaz et al. demonstrated that the gut microbiota plays a critical role. Numerous studies have highlighted the role of the gut microbiota in colorectal carcinogenesis. Specifically, several bacterial species, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and pks+ Escherichia coli are enriched in human CRC.7Yu A.I. Chen G.Y. The Gut Microbiome and Colorectal Cancer.in: Sun J. Inflammation, Infection, and Microbiome in Cancers. Springer, Cham, 2021: 63-96Crossref Google Scholar These oncomicrobes have been shown to promote tumorigenesis in preclinical models via several mechanisms including genotoxicity, dysregulation of Wnt signaling via β-catenin activation, and upregulation of pro-inflammatory signaling pathways.7Yu A.I. Chen G.Y. The Gut Microbiome and Colorectal Cancer.in: Sun J. Inflammation, Infection, and Microbiome in Cancers. Springer, Cham, 2021: 63-96Crossref Google Scholar In the study by Beyaz et al., a new mechanism was revealed, namely regulation of ISC MHC class II expression (Figure 1).3Beyaz S. Chung C. Mou H. Bauer-Rowe K.E. Xifaras M.E. Ergin I. Dohnalova L. Biton M. Shekhar K. Eskiocak O. et al.Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis.Cell Stem Cell. 2021; 28: 1922-1935 e5Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar In particular, Beyaz et al. showed that HFDs resulted in changes in the composition of the gut microbiota, including a significant decrease in the abundance of Helicobacter and Odoribacter spp. Co-housing and fecal transplantation studies using Helicobacter-positive and Helicobacter-negative donors confirmed the direct correlation between Helicobacter abundance and intestinal epithelial MHC class II expression levels. Future work involving monoassociation studies in gnotobiotic mice will be needed to further clarify the role of Helicobacter as well as other bacterial populations whose abundance is affected by HFDs in the regulation of ISC MHC class II expression, immune surveillance, and tumor susceptibility.To determine how the gut microbiota modulates MHC class II expression in ISCs, Beyaz et al. measured levels of innate immune receptors that are capable of sensing gut microbes and observed that a HFD diet reduced the expression of Toll-like receptor (Tlr) 2 and nucleotide-binding oligomerization domain (Nod) 2. In addition, HFD-fed mice exhibited reduced intestinal interferon-gamma (IFNγ) levels, and bulk RNA-seq of ISCs revealed downregulation of IFNγ-induced genes. Treatment of HFD-fed mice with a dual TLR2/NOD2 agonist or IFNγ increased MHC class II expression in ISCs. These findings are in line with previous evidence showing that the gut microbiota regulates the intestinal expression of TLR2 and NOD2, and that TLR-mediated expression of MHC class II requires IFNγ production by lamina propria lymphocytes.8Petnicki-Ocwieja T. Hrncir T. Liu Y.J. Biswas A. Hudcovic T. Tlaskalova-Hogenova H. Kobayashi K.S. Nod2 is required for the regulation of commensal microbiota in the intestine.Proc. Natl. Acad. Sci. USA. 2009; 106: 15813-15818Crossref PubMed Scopus (438) Google Scholar, 9Hörmann N. Brandão I. Jäckel S. Ens N. Lillich M. Walter U. Reinhardt C. Gut microbial colonization orchestrates TLR2 expression, signaling and epithelial proliferation in the small intestinal mucosa.PLoS ONE. 2014; 9: e113080Crossref PubMed Scopus (72) Google Scholar, 10Koyama M. Mukhopadhyay P. Schuster I.S. Henden A.S. Hulsdunker J. Varelias A. Vetizou M. Kuns R.D. Robb R.J. Zhan P. et al.MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota.Immunity. 2019; 51: 885-898 e7Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Altogether, these findings highlight the interplay between diet, the gut microbiota, and the host immune system on CRC susceptibility and support the incorporation of dietary strategies to promote anti-tumor immunity. Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related mortality worldwide. CRC has typically been a disease associated with increasing age, and heightened screening has resulted in a decline in CRC incidence in older individuals. However, there has been an alarming increase in early-onset colorectal cancers in individuals less than 50 years of age. Thus, there is a clear need to identify and mitigate risk factors, particularly lifestyle factors, that contribute to colorectal carcinogenesis. A hallmark of colorectal carcinogenesis is dysregulation of Wnt signaling and expansion of stem-like cells, marked by expression of Lgr5. Obesity and a high-fat diet (HFD) have been associated with increased risk for developing CRC, but the mechanism behind this association remains to be fully understood. Beyaz et al. had previously demonstrated that an HFD can drive Lgr5+ intestinal stem cell (ISC) proliferation and their capacity to self-renew via peroxisome proliferator-activated receptor-delta (PPAR-δ) signaling1Beyaz S. Mana M.D. Roper J. Kedrin D. Saadatpour A. Hong S.J. Bauer-Rowe K.E. Xifaras M.E. Akkad A. Arias E. et al.High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.Nature. 2016; 531: 53-58Crossref PubMed Scopus (391) Google Scholar. A HFD has also been associated with pathologic changes in the composition of the gut microbiota, known as dysbiosis, that can directly contribute to colorectal tumorigenesis2Yang J. Wei H. Zhou Y. Szeto C.H. Li C. Lin Y. Coker O.O. Lau H.C.H. Chan A.W.H. Sung J.J.Y. Yu J. High-Fat Diet Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites.Gastroenterology. 2021; (Published online August 27, 2021)https://doi.org/10.1053/j.gastro.2021.08.041Abstract Full Text Full Text PDF Scopus (35) Google Scholar. Recently, Beyaz et al.3Beyaz S. Chung C. Mou H. Bauer-Rowe K.E. Xifaras M.E. Ergin I. Dohnalova L. Biton M. Shekhar K. Eskiocak O. et al.Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis.Cell Stem Cell. 2021; 28: 1922-1935 e5Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar discovered a new mechanism linking diet and CRC risk via gut microbiota-mediated modulation of anti-tumor immunity. An essential step in immune surveillance is the presentation of tumor antigen via major histocompatibility complex (MHC) class I and MHC class II on the cell surface of antigen-presenting cells for recognition by CD8 and CD4 T cells, respectively, that lead to their activation. Although cytotoxic CD8 T cells have been considered the major players in immune surveillance, CD4 T cells also play a critical role in anti-tumor immunity via secretion of effector cytokines and promotion of CD8 cytotoxic T cell responses. Consistently, high MHC class II expression has been associated with better prognosis in CRC patients while loss of expression correlated with reduced tumor-infiltrating T cells and higher metastatic potential.4Sconocchia G. Eppenberger-Castori S. Zlobec I. Karamitopoulou E. Arriga R. Coppola A. Caratelli S. Spagnoli G.C. Lauro D. Lugli A. et al.HLA class II antigen expression in colorectal carcinoma tumors as a favorable prognostic marker.Neoplasia. 2014; 16: 31-42Crossref PubMed Scopus (72) Google Scholar,5Warabi M. Kitagawa M. Hirokawa K. Loss of MHC class II expression is associated with a decrease of tumor-infiltrating T cells and an increase of metastatic potential of colorectal cancer: immunohistological and histopathological analyses as compared with normal colonic mucosa and adenomas.Pathol. Res. Pract. 2000; 196: 807-815Crossref PubMed Scopus (30) Google Scholar In a kras-driven mouse model of intestinal cancer, a HFD altered the gut microbiome, which, in turn, resulted in reduced MHC class II expression on dendritic cells and increased tumorigenesis.6Schulz M.D. Atay C. Heringer J. Romrig F.K. Schwitalla S. Aydin B. Ziegler P.K. Varga J. Reindl W. Pommerenke C. et al.High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity.Nature. 2014; 514: 508-512Crossref PubMed Scopus (285) Google Scholar Beyaz et al. found that HFDs reduced MHC class II expression in intestinal epithelial cells, and in particular, in ISCs, that was independent of PPAR-δ signaling and obesity that was not diet-related.3Beyaz S. Chung C. Mou H. Bauer-Rowe K.E. Xifaras M.E. Ergin I. Dohnalova L. Biton M. Shekhar K. Eskiocak O. et al.Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis.Cell Stem Cell. 2021; 28: 1922-1935 e5Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Using an orthotopic mouse model of CRC in which Lgr5+ ISCs with loss of the tumor suppressor Apc are implanted into the colon, Beyaz et al. demonstrated that MHC class II-negative ISCs exhibited greater tumor-initiating capacity than their MHC class II-positive counterparts in HFD-fed mice. Furthermore, in mice that had loss of APC as well as MHC class II expression in Lgr5+ ISCs, larger tumors developed compared with mice that had intact MHC class II expression. MHC class II-related effects in Lgr5+ ISCs on tumorigenesis were not cell-intrinsic and did not involve stemness, as MHC class II-deficient APC-null Lgr5+ ISCs were still capable of forming tumor organoids in vitro and had similar organoid forming efficiencies to that of their MHC class II-expressing counterparts. Rather, the effects on tumorigenesis required the presence of B and T cells that mediate adaptive immunity. These findings by Beyaz et al. are exciting in that they suggest a role for ISC MHC class II-mediated immune surveillance in suppressing carcinogenesis that can be modulated by the diet. How MHC class II expression in ISCs is regulated is not entirely known; however, Beyaz et al. demonstrated that the gut microbiota plays a critical role. Numerous studies have highlighted the role of the gut microbiota in colorectal carcinogenesis. Specifically, several bacterial species, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and pks+ Escherichia coli are enriched in human CRC.7Yu A.I. Chen G.Y. The Gut Microbiome and Colorectal Cancer.in: Sun J. Inflammation, Infection, and Microbiome in Cancers. Springer, Cham, 2021: 63-96Crossref Google Scholar These oncomicrobes have been shown to promote tumorigenesis in preclinical models via several mechanisms including genotoxicity, dysregulation of Wnt signaling via β-catenin activation, and upregulation of pro-inflammatory signaling pathways.7Yu A.I. Chen G.Y. The Gut Microbiome and Colorectal Cancer.in: Sun J. Inflammation, Infection, and Microbiome in Cancers. Springer, Cham, 2021: 63-96Crossref Google Scholar In the study by Beyaz et al., a new mechanism was revealed, namely regulation of ISC MHC class II expression (Figure 1).3Beyaz S. Chung C. Mou H. Bauer-Rowe K.E. Xifaras M.E. Ergin I. Dohnalova L. Biton M. Shekhar K. Eskiocak O. et al.Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis.Cell Stem Cell. 2021; 28: 1922-1935 e5Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar In particular, Beyaz et al. showed that HFDs resulted in changes in the composition of the gut microbiota, including a significant decrease in the abundance of Helicobacter and Odoribacter spp. Co-housing and fecal transplantation studies using Helicobacter-positive and Helicobacter-negative donors confirmed the direct correlation between Helicobacter abundance and intestinal epithelial MHC class II expression levels. Future work involving monoassociation studies in gnotobiotic mice will be needed to further clarify the role of Helicobacter as well as other bacterial populations whose abundance is affected by HFDs in the regulation of ISC MHC class II expression, immune surveillance, and tumor susceptibility. To determine how the gut microbiota modulates MHC class II expression in ISCs, Beyaz et al. measured levels of innate immune receptors that are capable of sensing gut microbes and observed that a HFD diet reduced the expression of Toll-like receptor (Tlr) 2 and nucleotide-binding oligomerization domain (Nod) 2. In addition, HFD-fed mice exhibited reduced intestinal interferon-gamma (IFNγ) levels, and bulk RNA-seq of ISCs revealed downregulation of IFNγ-induced genes. Treatment of HFD-fed mice with a dual TLR2/NOD2 agonist or IFNγ increased MHC class II expression in ISCs. These findings are in line with previous evidence showing that the gut microbiota regulates the intestinal expression of TLR2 and NOD2, and that TLR-mediated expression of MHC class II requires IFNγ production by lamina propria lymphocytes.8Petnicki-Ocwieja T. Hrncir T. Liu Y.J. Biswas A. Hudcovic T. Tlaskalova-Hogenova H. Kobayashi K.S. Nod2 is required for the regulation of commensal microbiota in the intestine.Proc. Natl. Acad. Sci. USA. 2009; 106: 15813-15818Crossref PubMed Scopus (438) Google Scholar, 9Hörmann N. Brandão I. Jäckel S. Ens N. Lillich M. Walter U. Reinhardt C. Gut microbial colonization orchestrates TLR2 expression, signaling and epithelial proliferation in the small intestinal mucosa.PLoS ONE. 2014; 9: e113080Crossref PubMed Scopus (72) Google Scholar, 10Koyama M. Mukhopadhyay P. Schuster I.S. Henden A.S. Hulsdunker J. Varelias A. Vetizou M. Kuns R.D. Robb R.J. Zhan P. et al.MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota.Immunity. 2019; 51: 885-898 e7Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Altogether, these findings highlight the interplay between diet, the gut microbiota, and the host immune system on CRC susceptibility and support the incorporation of dietary strategies to promote anti-tumor immunity. Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesisBeyaz et al.Cell Stem CellSeptember 15, 2021In BriefThe mechanisms that link pro-obesity high-fat diets (HFDs) to increased colon cancer risk are not well understood. Beyaz and colleagues demonstrate that a HFD promotes intestinal tumor initiation by suppressing microbiome-stem cell-immune cell crosstalk that is mediated by MHC class II expression on intestinal stem cells. Full-Text PDF