Abstract
BackgroundCD8+ 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.MethodsWe 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.ResultsCompared 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.ConclusionsCD8+ 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.
Highlights
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and is the third leading cause of malignant tumor-related death
Our results showed that the accumulation of CD8+ T cells in advanced-stage tumor was systematically inhibited by Th17 cells via IL-17A/STAT3/CXCR3 axis
CD8+ T cell density was found lower in advanced-stage tumor tissues compared with early-stage tumor tissues, and high expression of CD8 was associated with a favorable prognosis (Fig. 1a–c)
Summary
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and is the third leading cause of malignant tumor-related death. Several preclinical and clinical studies have suggested that increased CD8+ T cell infiltration is correlated with a better prognosis for CRC patients [1,2,3,4]. Patients with hot tumors, displaying a high degree of T cell infiltration, exhibit better responses to immune checkpoint blockade [6, 7]. Tumor-infiltrating CD8+ T cells are considered the major effector immune cells in antitumor immunity [8, 9]. The mechanisms underlying CD8+ T cell infiltration in tumor remains unclear. CD8+ T cell trafficking to the tumor site is essential for effective colorectal cancer (CRC) immunotherapy. The mechanism underlying CD8+ T cell infiltration in colorectal tumor tissues is not fully understood. We investigated CD8+ T cell infiltration in CRC tissues and the role of chemokine– chemokine receptor signaling in regulation of T cell recruitment
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