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 chemokinechemokine receptor signaling in regulation of T cell recruitment. Methods: We screened chemokines and cytokines in healthy donor and CRC tissues from early-and advancedstage 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 advancedstage 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.

Irradiation Mediates IFNα and CXCL9 Expression in Non-Small Cell Lung Cancer to Stimulate CD8+ T Cells Activity and Migration toward Tumors

“…CXCR3 and CXCR4 are the genes that respond to CD8 + T cell trafficking [23]; CXCR3 was selected for further investigation since we found that its ligand CXCL9 was overexpressed in the irradiated A549 cells. We demonstrated that CXCR3 decreased in the CD8 + T cells of patients with lung cancer compared to those of healthy volunteers (Figure 4B), which has also been reported previously in patients with colorectal cancer [31]. Previous studies have demonstrated that CXCR3 −/− mice fail to facilitate CD8 + T cell migration without eliciting an anti-tumor immune response [32].…”

CD2+ T-helper 17-like cells differentiated from a CD133+ subpopulation of non-small cell lung carcinoma cells promote the growth of lung carcinoma

“…The levels of retinoic acid RORγt and interferon regulatory factor 4 (IFR4) genes, which are specific transcription factors of Th17 cells, were significantly higher in CD2 + cells (Figure 6C). The same was true for the gene expression of the cytokines IL-17A and IL-22 (Figure 6D), the production of which by Th17 cells triggers inflammatory signaling cascades and increases NSCLC cell proliferation, migration, and invasion (23)(24)(25). Subsequently, the secretions of IL-17A and IL-22 in CD2 + and CD2 − cell culture supernatants were detected by ELISA.…”

Resolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the Microbiota

“…Moreover, Th17 cells through the secretion of IL-17A and the transduction of the STAT3 pathway lead to the downregulation of CXCR3 expression on CD8 + T cells. Consequently, these Th17 cells dampen the CXCL10-dependent recruitment of cytotoxic CD8 + T cells (CTLs) in advanced stages of CRC ( 21 ). In addition, the IL-17R signaling in tumor cells blunts CXCL10 release thereby limiting CTLs influx in tumor bed ( 22 ).…”