Enhanced gut barrier integrity sensitizes colon cancer to immune therapy
Oral IL-10 suppressed tumor growth in the APCmin/+ mouse/Bacteroides fragilis colon cancer model while a similar formulation of IL-12 exacerbated disease. In contrast, combined treatment with IL-10 and IL-12 resulted in near-complete tumor eradication and a significant extension of survival. The cyt...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-11-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2018.1498438 |
| _version_ | 1819075382440099840 |
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| author | Neal Bhutiani Qingsheng Li Charles D. Anderson Heather C. Gallagher Magdia De Jesus Rajbir Singh Venkatkrishna R. Jala Mostafa Fraig Tao Gu Nejat K. Egilmez |
| author_facet | Neal Bhutiani Qingsheng Li Charles D. Anderson Heather C. Gallagher Magdia De Jesus Rajbir Singh Venkatkrishna R. Jala Mostafa Fraig Tao Gu Nejat K. Egilmez |
| author_sort | Neal Bhutiani |
| collection | DOAJ |
| description | Oral IL-10 suppressed tumor growth in the APCmin/+ mouse/Bacteroides fragilis colon cancer model while a similar formulation of IL-12 exacerbated disease. In contrast, combined treatment with IL-10 and IL-12 resulted in near-complete tumor eradication and a significant extension of survival. The cytokines mediated distinct immunological effects in the gut, i.e. IL-10 diminished Th17 cell prevalence whereas IL-12 induced IFNγ and enhanced CD8 + T-cell activity. Loss-of-function studies demonstrated that IL-12-driven CD8 + T-cell expansion was only partially responsible for the synergy, and that both the detrimental and the beneficial activities of IL-12 required IFNγ. Examination of colon physiology in mice receiving single vs dual treatment revealed that exacerbation of disease by IL-12 monotherapy was associated with compromised gut barrier integrity whereas combined treatment reversed this effect, uncovering additional activity by the cytokines on the stroma. Further analysis showed that the stromal effects of IL-12 included a 6-fold increase in IL-10RA expression in the colon epithelium, linking the epithelial activity of the cytokines. Finally, dual but not monotherapy induced a 3-fold increase in tight junction protein levels in the colon, identifying the mechanism by which IL-10 blocked the detrimental effect of the IL-12-IFNγ axis on barrier function without interfering with its beneficial immunological activity. These findings establish that the synergy between IL-12 and IL-10 was mediated by pleiotropic effects on the immune and the non-immune compartments and that the latter activity was critical to therapeutic outcome. |
| first_indexed | 2024-12-21T18:24:31Z |
| format | Article |
| id | doaj.art-cb834cdca9a34db9935ea5558df15a0d |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-21T18:24:31Z |
| publishDate | 2018-11-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-cb834cdca9a34db9935ea5558df15a0d2022-12-21T18:54:27ZengTaylor & Francis GroupOncoImmunology2162-402X2018-11-0171110.1080/2162402X.2018.14984381498438Enhanced gut barrier integrity sensitizes colon cancer to immune therapyNeal Bhutiani0Qingsheng Li1Charles D. Anderson2Heather C. Gallagher3Magdia De Jesus4Rajbir Singh5Venkatkrishna R. Jala6Mostafa Fraig7Tao Gu8Nejat K. Egilmez9School of Medicine, University of LouisvilleSchool of Medicine, University of LouisvilleSchool of Medicine, University of LouisvilleUniversity at Albany School of Public Health, One University Place RensselaerUniversity at Albany School of Public Health, One University Place RensselaerSchool of Medicine, University of LouisvilleSchool of Medicine, University of LouisvilleSchool of Medicine, University of LouisvilleSchool of Medicine, University of LouisvilleSchool of Medicine, University of LouisvilleOral IL-10 suppressed tumor growth in the APCmin/+ mouse/Bacteroides fragilis colon cancer model while a similar formulation of IL-12 exacerbated disease. In contrast, combined treatment with IL-10 and IL-12 resulted in near-complete tumor eradication and a significant extension of survival. The cytokines mediated distinct immunological effects in the gut, i.e. IL-10 diminished Th17 cell prevalence whereas IL-12 induced IFNγ and enhanced CD8 + T-cell activity. Loss-of-function studies demonstrated that IL-12-driven CD8 + T-cell expansion was only partially responsible for the synergy, and that both the detrimental and the beneficial activities of IL-12 required IFNγ. Examination of colon physiology in mice receiving single vs dual treatment revealed that exacerbation of disease by IL-12 monotherapy was associated with compromised gut barrier integrity whereas combined treatment reversed this effect, uncovering additional activity by the cytokines on the stroma. Further analysis showed that the stromal effects of IL-12 included a 6-fold increase in IL-10RA expression in the colon epithelium, linking the epithelial activity of the cytokines. Finally, dual but not monotherapy induced a 3-fold increase in tight junction protein levels in the colon, identifying the mechanism by which IL-10 blocked the detrimental effect of the IL-12-IFNγ axis on barrier function without interfering with its beneficial immunological activity. These findings establish that the synergy between IL-12 and IL-10 was mediated by pleiotropic effects on the immune and the non-immune compartments and that the latter activity was critical to therapeutic outcome.http://dx.doi.org/10.1080/2162402X.2018.1498438il-10il-12il-17colon cancergut epithelial barrier |
| spellingShingle | Neal Bhutiani Qingsheng Li Charles D. Anderson Heather C. Gallagher Magdia De Jesus Rajbir Singh Venkatkrishna R. Jala Mostafa Fraig Tao Gu Nejat K. Egilmez Enhanced gut barrier integrity sensitizes colon cancer to immune therapy OncoImmunology il-10 il-12 il-17 colon cancer gut epithelial barrier |
| title | Enhanced gut barrier integrity sensitizes colon cancer to immune therapy |
| title_full | Enhanced gut barrier integrity sensitizes colon cancer to immune therapy |
| title_fullStr | Enhanced gut barrier integrity sensitizes colon cancer to immune therapy |
| title_full_unstemmed | Enhanced gut barrier integrity sensitizes colon cancer to immune therapy |
| title_short | Enhanced gut barrier integrity sensitizes colon cancer to immune therapy |
| title_sort | enhanced gut barrier integrity sensitizes colon cancer to immune therapy |
| topic | il-10 il-12 il-17 colon cancer gut epithelial barrier |
| url | http://dx.doi.org/10.1080/2162402X.2018.1498438 |
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