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??T17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer.

ABSTRACT: Development of cancer has been linked to chronic inflammation, particularly via interleukin-23 (IL-23) and IL-17 signaling pathways. However, the cellular source of IL-17 and underlying mechanisms by which IL-17-producing cells promote human colorectal cancer (CRC) remain poorly defined. Here, we demonstrate that innate ??T (??T17) cells are the major cellular source of IL-17 in human CRC. Microbial products elicited by tumorous epithelial barrier disruption correlated with inflammatory dendritic cell (inf-DC) accumulation and ??T17 polarization in human tumors. Activated inf-DCs induced ??T17 cells to secrete IL-8, tumor necrosis factor alpha, and GM-CSF with a concomitant accumulation of immunosuppressive PMN-MDSCs in the tumor. Importantly, ??T17 cell infiltration positively correlated with tumor stages and other clinicopathological features. Our study uncovers an inf-DC-??T17-PMN-MDSC regulatory axis in human CRC that correlates MDSC-meditated immunosuppression with tumor-elicited inflammation. These findings suggest that ??T17 cells might be key players in human CRC progression and have the potential for treatment or prognosis prediction.

SUBMITTER: Wu P

PROVIDER: S-EPMC4716654 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer.

Wu Pin P Wu Dang D Ni Chao C Ye Jun J Chen Wuzhen W Hu Guoming G Wang Zhen Z Wang Changrong C Zhang Zhigang Z Xia Wenjie W Chen Zhigang Z Wang Ke K Zhang Tao T Xu Jinghong J Han Yuehua Y Zhang Ting T Wu Xianguo X Wang Jianwei J Gong Weihua W Zheng Shu S Qiu Fuming F Yan Jun J Huang Jian J

Immunity 20140508 5

Development of cancer has been linked to chronic inflammation, particularly via interleukin-23 (IL-23) and IL-17 signaling pathways. However, the cellular source of IL-17 and underlying mechanisms by which IL-17-producing cells promote human colorectal cancer (CRC) remain poorly defined. Here, we demonstrate that innate γδT (γδT17) cells are the major cellular source of IL-17 in human CRC. Microbial products elicited by tumorous epithelial barrier disruption correlated with inflammatory dendriti ...[more]

PMID: 24816404

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Project description:Aging results in enhanced myelopoiesis, which is associated with an increased prevalence of myeloid leukemias and the production of myeloid-derived suppressor cells (MDSCs). Tristetraprolin (TTP) is an RNA binding protein that regulates immune-related cytokines and chemokines by destabilizing target mRNAs. As TTP expression is known to decrease with age in myeloid cells, we used TTP-deficient (TTPKO) mice to model aged mice to study TTP regulation in age-related myelopoiesis. Both TTPKO and myeloid-specific TTPKO (cTTPKO) mice had significant increases in both MDSC subpopulations M-MDSCs (CD11b+Ly6ChiLy6G-) and PMN-MDSCs (CD11b+Ly6CloLy6G+), as well as macrophages (CD11b+F4/80+) in the spleen and mesenteric lymph nodes; however, no quantitative changes in MDSCs were observed in the bone marrow. In contrast, gain-of-function TTP knock-in (TTPKI) mice had no change in MDSCs compared with control mice. Within the bone marrow, total granulocyte-monocyte progenitors (GMPs) and monocyte progenitors (MPs), direct antecedents of M-MDSCs, were significantly increased in both cTTPKO and TTPKO mice, but granulocyte progenitors (GPs) were significantly increased only in TTPKO mice. Transcriptomic analysis of the bone marrow myeloid cell populations revealed that the expression of CC chemokine receptor 2 (CCR2), which plays a key role in monocyte mobilization to inflammatory sites, was dramatically increased in both cTTPKO and TTPKO mice. Concurrently, the concentration of CC chemokine ligand 2 (CCL2), a major ligand of CCR2, was high in the serum of cTTPKO and TTPKO mice, suggesting that TTP impacts the mobilization of M-MDSCs from the bone marrow to inflammatory sites during aging via regulation of the CCR2-CCL2 axis. Collectively, these studies demonstrate a previously unrecognized role for TTP in regulating age-associated myelopoiesis through the expansion of specific myeloid progenitors and M-MDSCs and their recruitment to sites of injury, inflammation, or other pathologic perturbations.

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Dataset Information

??T17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer.

Publications

γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer.

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