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

• Published in: Journal of hematology and oncology 2020-06, Vol.13 (1), p.68-68, Article 68
• Main Authors: Wang, Dan, Yu, Weina, Lian, Jingyao, Wu, Qian, Liu, Shasha, Yang, Li, Li, Feng, Huang, Lan, Chen, Xinfeng, Zhang, Zhen, Li, Aitian, Liu, Jinbo, Sun, Zhenqiang, Wang, Junxia, Yuan, Weitang, Zhang, Yi
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - immunology; Adenocarcinoma - pathology; Adult; Aged; Analysis; Animals; Antibodies; 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 carcinoma; 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; 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
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-020-00897-z

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. 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. 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. 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.