Smad4-deficient T cells promote colitis-associated colon cancer via an IFN-γ-dependent suppression of 15-hydroxyprostaglandin dehydrogenase
Immune cells and the cytokines they produce are important mediators of the transition from colitis to colon cancer, but the mechanisms mediating this disease progression are poorly understood. Interferon gamma (IFN-γ) is known to contribute to the pathogenesis of colitis through immune modulatory me...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.932412/full |
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| author | Sung Hee Choi Sung Hee Choi Alex Y. Huang Alex Y. Huang Alex Y. Huang John J. Letterio John J. Letterio John J. Letterio Byung-Gyu Kim Byung-Gyu Kim |
| author_facet | Sung Hee Choi Sung Hee Choi Alex Y. Huang Alex Y. Huang Alex Y. Huang John J. Letterio John J. Letterio John J. Letterio Byung-Gyu Kim Byung-Gyu Kim |
| author_sort | Sung Hee Choi |
| collection | DOAJ |
| description | Immune cells and the cytokines they produce are important mediators of the transition from colitis to colon cancer, but the mechanisms mediating this disease progression are poorly understood. Interferon gamma (IFN-γ) is known to contribute to the pathogenesis of colitis through immune modulatory mechanisms, and through direct effects on endothelial and epithelial homeostasis. Here we explore whether IFN-γ influences tumor progression by expanding the effector memory T cells (TEM) population and restricting the expression of tumor suppressors in a preclinical model of spontaneous colitis-associated colorectal cancer (CAC). We show that IFN-γ expression is significantly increased both in the T cells and the colonic mucosal epithelia of mice with a T cell-restricted deletion of the TGF-β intermediate, SMAD4 (Smad4TKO). The increase of IFN-γ expression correlates with the onset of spontaneous CAC in Smad4TKO mice by 6 months of age. This phenotype is greatly ameliorated by the introduction of a germline deletion of IFN-γ in Smad4TKO mice (Smad4TKO/IFN-γKO, DKO). DKO mice had a significantly reduced incidence and progression of CAC, and a decrease in the number of mucosal CD4+ TEM cells, when compared to those of Smad4TKO mice. Similarly, the colon epithelia of DKO mice exhibited a non-oncogenic signature with a decrease in the expression of iNOS and p-STAT1, and a restoration of the tumor suppressor gene, 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In vitro, treatment of human colon cancer cells with IFN-γ decreased the expression of 15-PGDH. Our data suggest that Smad4-deficient T cells promote CAC through mechanisms that include an IFN-γ-dependent suppression of the tumor suppressor 15-PGDH. |
| first_indexed | 2024-04-13T13:06:29Z |
| format | Article |
| id | doaj.art-30005d0442ce41d38e4e231d7c855416 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T13:06:29Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-30005d0442ce41d38e4e231d7c8554162022-12-22T02:45:46ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-08-011310.3389/fimmu.2022.932412932412Smad4-deficient T cells promote colitis-associated colon cancer via an IFN-γ-dependent suppression of 15-hydroxyprostaglandin dehydrogenaseSung Hee Choi0Sung Hee Choi1Alex Y. Huang2Alex Y. Huang3Alex Y. Huang4John J. Letterio5John J. Letterio6John J. Letterio7Byung-Gyu Kim8Byung-Gyu Kim9Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, United StatesCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, United StatesThe Angie Fowler Adolescent and Young Adult Cancer Institute, University Hospitals (UH) Rainbow Babies and Children’s Hospital, Cleveland, OH, United StatesCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, United StatesThe Angie Fowler Adolescent and Young Adult Cancer Institute, University Hospitals (UH) Rainbow Babies and Children’s Hospital, Cleveland, OH, United StatesCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, United StatesImmune cells and the cytokines they produce are important mediators of the transition from colitis to colon cancer, but the mechanisms mediating this disease progression are poorly understood. Interferon gamma (IFN-γ) is known to contribute to the pathogenesis of colitis through immune modulatory mechanisms, and through direct effects on endothelial and epithelial homeostasis. Here we explore whether IFN-γ influences tumor progression by expanding the effector memory T cells (TEM) population and restricting the expression of tumor suppressors in a preclinical model of spontaneous colitis-associated colorectal cancer (CAC). We show that IFN-γ expression is significantly increased both in the T cells and the colonic mucosal epithelia of mice with a T cell-restricted deletion of the TGF-β intermediate, SMAD4 (Smad4TKO). The increase of IFN-γ expression correlates with the onset of spontaneous CAC in Smad4TKO mice by 6 months of age. This phenotype is greatly ameliorated by the introduction of a germline deletion of IFN-γ in Smad4TKO mice (Smad4TKO/IFN-γKO, DKO). DKO mice had a significantly reduced incidence and progression of CAC, and a decrease in the number of mucosal CD4+ TEM cells, when compared to those of Smad4TKO mice. Similarly, the colon epithelia of DKO mice exhibited a non-oncogenic signature with a decrease in the expression of iNOS and p-STAT1, and a restoration of the tumor suppressor gene, 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In vitro, treatment of human colon cancer cells with IFN-γ decreased the expression of 15-PGDH. Our data suggest that Smad4-deficient T cells promote CAC through mechanisms that include an IFN-γ-dependent suppression of the tumor suppressor 15-PGDH.https://www.frontiersin.org/articles/10.3389/fimmu.2022.932412/fullIFN-gammaSmad4CD4 effector T cell15-PGDHcolitis-associated colon cancer |
| spellingShingle | Sung Hee Choi Sung Hee Choi Alex Y. Huang Alex Y. Huang Alex Y. Huang John J. Letterio John J. Letterio John J. Letterio Byung-Gyu Kim Byung-Gyu Kim Smad4-deficient T cells promote colitis-associated colon cancer via an IFN-γ-dependent suppression of 15-hydroxyprostaglandin dehydrogenase Frontiers in Immunology IFN-gamma Smad4 CD4 effector T cell 15-PGDH colitis-associated colon cancer |
| title | Smad4-deficient T cells promote colitis-associated colon cancer via an IFN-γ-dependent suppression of 15-hydroxyprostaglandin dehydrogenase |
| title_full | Smad4-deficient T cells promote colitis-associated colon cancer via an IFN-γ-dependent suppression of 15-hydroxyprostaglandin dehydrogenase |
| title_fullStr | Smad4-deficient T cells promote colitis-associated colon cancer via an IFN-γ-dependent suppression of 15-hydroxyprostaglandin dehydrogenase |
| title_full_unstemmed | Smad4-deficient T cells promote colitis-associated colon cancer via an IFN-γ-dependent suppression of 15-hydroxyprostaglandin dehydrogenase |
| title_short | Smad4-deficient T cells promote colitis-associated colon cancer via an IFN-γ-dependent suppression of 15-hydroxyprostaglandin dehydrogenase |
| title_sort | smad4 deficient t cells promote colitis associated colon cancer via an ifn γ dependent suppression of 15 hydroxyprostaglandin dehydrogenase |
| topic | IFN-gamma Smad4 CD4 effector T cell 15-PGDH colitis-associated colon cancer |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.932412/full |
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