[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment

Cancer Res. 2015 Feb 1;75(3):508-518. doi: 10.1158/0008-5472.CAN-14-1215. Epub 2014 Dec 5.

Abstract

Immune rejection of tumors is mediated by IFNγ production and T-cell cytolytic activity. These processes are impeded by PD-1, a coinhibitory molecule expressed on T cells that is elevated in tumor-infiltrating lymphocytes (TIL). PD-1 elevation may reflect T-cell exhaustion marked by decreased proliferation, production of type I cytokines, and poor cytolytic activity. Although anti-PD-1 antibodies enhance IFNγ secretion after stimulation of the T-cell receptor (TCR), the mechanistic link between PD-1 and its effects on T-cell help (Tc1/Th1 skewing) remains unclear. In prospectively collected cancer tissues, we found that TIL exhibited dampened Tc1/Th1 skewing and activation compared with peripheral blood lymphocytes (PBL). When PD-1 bound its ligand PD-L1, we observed a marked suppression of critical TCR target genes and Th1 cytokines. Conversely, PD-1 blockade reversed these suppressive effects of PD-1:PD-L1 ligation. We also found that the TCR-regulated phosphatase SHP-2 was expressed higher in TIL than in PBL, tightly correlating with PD-1 expression and negative regulation of TCR target genes. Overall, these results defined a PD-1/SHP-2/STAT1/T-bet signaling axis mediating the suppressive effects of PD-1 on Th1 immunity at tumor sites. Our findings argue that PD-1 or SHP-2 blockade will be sufficient to restore robust Th1 immunity and T-cell activation and thereby reverse immunosuppression in the tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • CD4-Positive T-Lymphocytes / cytology
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / immunology*
  • Cytokines / metabolism
  • Female
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / immunology*
  • Humans
  • Immunosuppressive Agents
  • Immunotherapy / methods
  • Ligands
  • Lymphocytes / cytology
  • Lymphocytes, Tumor-Infiltrating / cytology
  • Male
  • Middle Aged
  • Neoplasms / metabolism
  • Programmed Cell Death 1 Receptor / metabolism*
  • Prospective Studies
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Squamous Cell Carcinoma of Head and Neck
  • Th1 Cells / cytology*
  • Tumor Microenvironment*

Substances

  • Cytokines
  • Immunosuppressive Agents
  • Ligands
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11