Journal of Hematology & Oncology (Jun 2020)

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

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

DOI
https://doi.org/10.1186/s13045-020-00897-z
Journal volume & issue
Vol. 13, no. 1
pp. 1 – 15

Abstract

Read online

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.

Keywords