Hu & Zhang Lab
The State Key Laboratory of Biotherapy Si-Chuan University

yδT Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

  The majority of T cells are αβT cells whose TCRs are composed of α and β chains, whereas 5-10% T cells are gamma-delta( γδ)T cells whose TCRs consists of γ and δ heterodimers. γδT cells are mainly located in mucosal associated lymph organ. The differents between αβ vs γδT cells are antigen recognition machanism. γδT cells are considered as the bridge of innate and adaptive immunity. γδT cells also play important role in tumor-immunology, they have long been considered as potent anti-tumor effectors in many tumor types. However recently study find that the γδT cells in PDA exhibit a unique phenotype which enhances tumorigenesis through immune suppression.

  In this study, Daley et al. identify 40% of tumor-infiltrating T cells in PDA are activated γδT cells. This γδT cell population in PDA inhibits activation of αβT cells by expressing T cell exhaustion ligands PD-L1 and Galectin-9. PD-L1 is well-known as the ligand of PD-1 which is an important immune suppressive molecule, and Galectin-9/Tim-3 pathway also has inhibitory effect on CD4, CD8 T cells and NK cells. CCR2, CCR5 and CCR6 are chemokine receptors which expressed by γδT cell, which are important for γδT cell recruitments and required for γδT cell expression of PD-L1 or Galectin-9,since PDA-infiltrating γδT cell express lower PD-L1 or Galectin-9 levels in CCR2–/–, CCR5–/–and CCR6–/–mice. γδT cells prevented CD4+ and CD8+ T cells activation ,indicated induced by CD44+ CD62L- population. Furthermore, PDA-infiltrating γδT cells prevented αβT cell expressing TNF-α. When blocking PD-L1 and Galectin-9 using neutralizing mAbs, the suppression of αβT cells in PDA mediated by γδT cell is rescued. Therefore PDA- infiltrating γδT cells inhibit αβT cells activation via checkpoint- ligand-dependent immune suppression.

   This study finds that PDA- infiltrating γδT cells promote pancreatic oncogenesis by inhibiting activation αβT cells, which provide new strategies for tumor-immune therapy targeting γδT cell in PDA. For example, blocking chemokine- chemokine receptor which is important for γδT cell recruitment ( CCR2, CCR5 and CCR6),and combining PD-L1blockage may reverse the immune-suppressive miroenvironment mediated by γδT cells in PDA.

By Xueying

ORIGINAL RESEARCH PAPER Daley et al. yδT Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation.2016, Cell 166, 1–15