Journal Article

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

Wang, Junxia, Liu, Shasha, Yu, Weina, Wang, Dan, Chen, Xinfeng, Zhang, Zhen, Yang, Li, Li, Feng, Wu, Qian, Liu, Jinbo, Zhang, Yi, Lian, Jingyao, Sun, Zhenqiang, Huang, Lan, Yuan, Weitang, Li, Aitian

2020

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenocarcinoma - immunology / Adenocarcinoma - pathology / Adult / Aged / Analysis / Animals / Antibodies / Cancer Research / Cancer treatment / CD8 / CD8 antigen / CD8 Antigens - biosynthesis / CD8 Antigens - genetics / CD8-Positive T-Lymphocytes - immunology / Cell adhesion & migration / Cell density / Cell migration / Cell Movement / Chemokine CXCL10 - physiology / Chemokines / Colorectal cancer / Colorectal Neoplasms - immunology / Colorectal Neoplasms - pathology / CXCL10 protein / CXCR3 / CXCR3 protein / Cyclic S-Oxides - pharmacology / Cytokines / Down-Regulation / Female / Flow cytometry / Gastrointestinal diseases / Helper cells / Hematology / Humans / IL-17A / Immunotherapy / Infiltration / Interleukin-17 - physiology / Kaplan-Meier Estimate / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - immunology / Male / Medical prognosis / Medicine / Medicine & Public Health / Metastases / Metastasis / Mice / Mice, Inbred BALB C / Mice, Nude / Middle Aged / Neoplasm Proteins - antagonists & inhibitors / Neoplasm Proteins - biosynthesis / Neoplasm Proteins - genetics / Neoplasm Proteins - physiology / Oncology / Patients / Peripheral blood / Random Allocation / Receptors, CXCR3 - biosynthesis / Receptors, CXCR3 - genetics / Receptors, CXCR3 - physiology / Stat3 protein / STAT3 Transcription Factor - antagonists & inhibitors / STAT3 Transcription Factor - physiology / T cells / Th17 cells / Th17 Cells - physiology / Transcription activation / Transcription factors / Tumors / Xenograft Model Antitumor Assays / Xenografts