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Th17 cells inhibit CD8+ T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients.


ABSTRACT: BACKGROUND:CD8+ T cell trafficking to the tumor site is essential for effective colorectal cancer (CRC) immunotherapy. However, the mechanism underlying CD8+ T cell infiltration in colorectal tumor tissues is not fully understood. In the present study, we investigated CD8+ T cell infiltration in CRC tissues and the role of chemokine-chemokine receptor signaling in regulation of T cell recruitment. METHODS:We screened chemokines and cytokines in healthy donor and CRC tissues from early- and advanced-stage patients using multiplex assays and PCR screening. We also utilized transcription factor activation profiling arrays and established a xenograft mouse model. RESULTS:Compared with tumor tissues of early-stage CRC patients, CD8+ T cell density was lower in advanced-stage tumor tissues. PCR screening showed that CXCL10 levels were significantly increased in advanced-stage tumor tissues. CXCR3 (the receptor of CXCL10) expression on CD8+ T cells was lower in the peripheral blood of advanced-stage patients. The migratory ability of CD8+ T cells to CXCL10 depended on CXCR3 expression. Multiplex arrays showed that IL-17A was increased in advanced-stage patient sera, which markedly downregulated CXCR3 expression via activating STAT3 signaling and reduced CD8+ T cell migration. Similar results were found after CD8+ T cells were treated with Th17 cell supernatant. Adding anti-IL-17A or the STAT3 inhibitor, Stattic, rescued these effects in vitro and in vivo. Moreover, survival analysis showed that patients with low CD8 and CXCR3 expression and high IL-17A levels had significantly worse prognosis. CONCLUSIONS:CD8+ T cell infiltration in advanced-stage tumor was systematically inhibited by Th17 cells via IL-17A/STAT3/CXCR3 axis. Our findings indicate that the T cell infiltration in the tumor microenvironment may be improved by inhibiting STAT3 signaling.

SUBMITTER: Wang D 

PROVIDER: S-EPMC7275425 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Th17 cells inhibit CD8<sup>+</sup> T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients.

Wang Dan D   Yu Weina W   Lian Jingyao J   Wu Qian Q   Liu Shasha S   Yang Li L   Li Feng F   Huang Lan L   Chen Xinfeng X   Zhang Zhen Z   Li Aitian A   Liu Jinbo J   Sun Zhenqiang Z   Wang Junxia J   Yuan Weitang W   Zhang Yi Y  

Journal of hematology & oncology 20200605 1


<h4>Background</h4>CD8<sup>+</sup> T cell trafficking to the tumor site is essential for effective colorectal cancer (CRC) immunotherapy. However, the mechanism underlying CD8<sup>+</sup> T cell infiltration in colorectal tumor tissues is not fully understood. In the present study, we investigated CD8<sup>+</sup> T cell infiltration in CRC tissues and the role of chemokine-chemokine receptor signaling in regulation of T cell recruitment.<h4>Methods</h4>We screened chemokines and cytokines in hea  ...[more]

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