Dataset Information

Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenicCD4⁺ T-cells and induction of antitumor CD8⁺ T-cell activity.

ABSTRACT: An oral sustained-release formulation of Interleukin-10 suppressed tumor growth and enhanced survival in the APC^min/+/Bacteroides fragilis spontaneous colon cancer model. Therapeutic benefit was associated with a 5-fold reduction in CD4⁺RORγt⁺Foxp3^-IL-17⁺ T-helper cell, CD4⁺RORγt⁺Foxp3⁺IL-17⁺ pathogenic T-regulatory cell and CD4⁺RORγt^-Foxp3⁺IL-17^- conventional T-regulatory cell numbers and a concurrent 2-fold enhancement in CD8⁺ T-cell activity in the colon. Selective subset depletion and functional blockade studies demonstrated that at steady-state CD4⁺RORγt⁺IL-17⁺ T-cell subsets and CD4⁺Foxp3⁺ cTreg supported tumorigenesis, whereas CD8⁺ cytotoxic T-lymphocytes impeded tumor progression following IL-10 therapy. Suppression of tumor growth by CD8⁺ T-cells was associated with enhanced tumor infiltration and cytotoxic granule exocytosis. These findings establish the utility of oral IL-10 as a potential new therapeutic in the management of colon cancer and shed light on the cellular mechanisms that underlie its antitumor activity.

SUBMITTER: Gu T

PROVIDER: S-EPMC5486184 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenicCD4+ T-cells and induction of antitumor CD8+ T-cell activity.

Gu Tao T De Jesus Magdia M Gallagher Heather C HC Burris Thomas P TP Egilmez Nejat K NK

Oncoimmunology 20170420 6

An oral sustained-release formulation of Interleukin-10 suppressed tumor growth and enhanced survival in the APCmin/+/Bacteroides fragilis spontaneous colon cancer model. Therapeutic benefit was associated with a 5-fold reduction in CD4+RORγt+Foxp3-IL-17+ T-helper cell, CD4+RORγt+Foxp3+IL-17+ pathogenic T-regulatory cell and CD4+RORγt-Foxp3+IL-17- ...[more]

PMID: 28680752

Similar Datasets

Project description:Background & aimsThe liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo.MethodsTo induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10.ResultsWe found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions.ConclusionsTreg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases.Impact and implicationsLiver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.

Dataset Information

Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenicCD4⁺ T-cells and induction of antitumor CD8⁺ T-cell activity.

Publications

Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenicCD4<sup>+</sup> T-cells and induction of antitumor CD8<sup>+</sup> T-cell activity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets