title: PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment.
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.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Hyun-Bae
authors.initials: HB
authors.lastname: Jie
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Gildener-Leapman
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Sumita
authors.initials: S
authors.lastname: Trivedi
authors.affiliation: University of Pittsburgh Health Sciences.
authors.forename: Tony
authors.initials: T
authors.lastname: Green
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Kane
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.|Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents; D007167:Immunotherapy / Q000379:methods; D008024:Ligands; D008214:Lymphocytes / Q000166:cytology; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D011446:Prospective Studies; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck; D018417:Th1 Cells / Q000166:cytology*; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D008024:Ligands; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11