Interleukin-10 attenuates tumour growth by inhibiting interleukin-6/signal transducer and activator of transcription 3 signalling in myeloid-derived suppressor cells

Lee, Bora; Kwon, Bo-Eun; Hong, Eock Kee; Shim, Aeri; Song, Jae-Hyoung; Kim, Hongmin; Chang, Shau‐Jin; Kim, Yeon Jeong; Kweon, Mi‐Na; Youn, Jang H.; Ko, Hyun‐Jeong

doi:10.1016/j.canlet.2016.07.012

Cited by 31 publications

(23 citation statements)

References 42 publications

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“…Analogously, genetic deletion of integrin-αM (also known as CD11b) in mice resulted in decreased recruitment of PMN-MDSCs to colorectal carcinomas and led to reduced tumor burden and improved survival, establishing integrin-αM as an additional therapeutic target ( 228 ). Similar findings were observed after inhibition of the IL-6/STAT3 pathways, leading to a significant inhibition of MDSC expansion and tumor growth of the murine TC1 tumor model ( 222 ). Also in mice, SAR131675, an inhibitor of VEGFR-3, led to a reduction in the frequency of MDSCs in the tumor and in the spleen ( 220 ).…”

Section: Myeloid-derived Suppressor Cellssupporting

confidence: 76%

Diamonds in the Rough: Harnessing Tumor-Associated Myeloid Cells for Cancer Therapy

et al. 2018

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Therapeutic approaches that engage immune cells to treat cancer are becoming increasingly utilized in the clinics and demonstrated durable clinical benefit in several solid tumor types. Most of the current immunotherapies focus on manipulating T cells, however, the tumor microenvironment (TME) is abundantly infiltrated by a heterogeneous population of tumor-associated myeloid cells, including tumor-associated macrophages (TAMs), tumor-associated dendritic cells (TADCs), tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs). Educated by signals perceived in the TME, these cells often acquire tumor-promoting properties ultimately favoring disease progression. Upon appropriate stimuli, myeloid cells can exhibit cytoxic, phagocytic, and antigen-presenting activities thereby bolstering antitumor immune responses. Thus, depletion, reprogramming or reactivation of myeloid cells to either directly eradicate malignant cells or promote antitumor T-cell responses is an emerging field of interest. In this review, we briefly discuss the tumor-promoting and tumor-suppressive roles of myeloid cells in the TME, and describe potential therapeutic strategies in preclinical and clinical development that aim to target them to further expand the range of current treatment options.

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Section: Myeloid-derived Suppressor Cellssupporting

confidence: 76%

Diamonds in the Rough: Harnessing Tumor-Associated Myeloid Cells for Cancer Therapy

et al. 2018

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“…The molecular link between IL-10 and DNMT3b is further validated by our observation in inflamed colon tissues that the deletion of IL-10 results in the loss of DNMT3b expression. Since it is known that IL-10 inhibits the IL-6-mediated STAT3 activation in MDSCs ( Lee et al, 2016a ), it is possible that IL-10 KO colon tissues express a high level of DNMT1 because IL-10 deficiency likely leads to increased IL-6 and resultant DNMT1 upregulation under conditions of chronic inflammation ( Li et al, 2012 ). Therefore, in contrast to IL-10 functioning as a suppressor of CAC, our data indicate that IL-10 plays a promoting role in chronic inflammation-mediated CAC.…”

Section: Discussionmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis

Ibrahim

Klement

et al. 2018

Cell Reports

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SUMMARY IL-10 functions as a suppressor of colitis and colitis-associated colon cancer, but it is also a risk locus associated with ulcerative colitis. The mechanism underlying the contrasting roles of IL-10 in inflammation and colon cancer is unknown. We report here that inflammation induces the accumulation of CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) that express high levels of IL-10 in colon tissue. IL-10 induces the activation of STAT3 that directly binds to the Dnmt1 and Dnmt3b promoters to activate their expression, resulting in DNA hypermethylation at the Irf8 promoter to silence IRF8 expression in colon epithelial cells. Mice with Irf8 deleted in colonic epithelial cells exhibit significantly higher inflammation-induced tumor incidence. Human colorectal carcinomas have significantly higher DNMT1 and DNMT3b and lower IRF8 expression, and they exhibit significantly higher IRF8 promoter DNA methylation than normal colon. Our data identify the MDSC-IL-10-STAT3-DNMT3b-IRF8 pathway as a link between chronic inflammation and colon cancer initiation.

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“…Many of these molecules signal through STAT3, which also upregulates S100A9, a myeloid-related protein that prevented DC maturation resulting in accumulation of MDSCs (21,103,166). IL-10, conversely, inhibited MDSC-expansion by blocking IL-6 signaling through STAT3 (83). Several of these and other proinflammatory and damage-associated signals are also upregulated during chronic viral infections, and may play analogous roles in MDSC expansion.…”

Section: Factors Involved In Mdsc Expansionmentioning

confidence: 99%

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

2017

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Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that are well described as potent immune regulatory cells during human cancer and murine tumor models. Reports of MDSCs during viral infections remain limited, and their association with immunomodulation of viral diseases is still being defined. Here, we provide an overview of MDSCs or MDSC-like cells identified during viral infections, including murine viral models and human viral diseases. Understanding the similarities and/or differences of virally induced versus tumor-derived MDSCs will be important for designing future immunotherapeutic approaches.

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Interleukin-10 attenuates tumour growth by inhibiting interleukin-6/signal transducer and activator of transcription 3 signalling in myeloid-derived suppressor cells

Cited by 31 publications

References 42 publications

Diamonds in the Rough: Harnessing Tumor-Associated Myeloid Cells for Cancer Therapy

Diamonds in the Rough: Harnessing Tumor-Associated Myeloid Cells for Cancer Therapy

Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

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