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 IFN-γ production and T cell cytolytic activity. These processes are impeded by PD-1, a co-inhibitory 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 1 cytokines and poor cytolytic activity. Although anti-PD-1 antibodies enhance IFN-γ 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 to 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.

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

“…20 In tumor immunology, it enables new ways of analyzing treatment responses in adaptive immunity, which is of importance as intratumoral T-cell populations have been demonstrated to crucially influence disease course. 21,22 TCR analysis can be performed on multiple samples from the same patient simultaneously, providing an overview of distinct T cell compositions, depending on the tissue origin. So far, differences in PBL and in TIL have been observed.…”

Tumor-infiltrating Tim-3+ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk

“…27 Nonetheless, how Tim-3 mediates suppression of T cell activation or effector function is poorly understood, even though Tim-3 has been recognized as an additional marker of exhaustion on PD-1 C T cells in cancers and chronic viral infection. Recently, Tim-3 was proposed to help drive T cell exhaustion by augmenting TCR/CD28 signaling, 26,38 since excessive and constitutive TCR signaling, especially mTORC1, has been suggested to be critical for the development of T cell exhaustion.…”

“…In contrast, PD-1:PD-L1 ligation has been shown to suppress TCR signaling, and to inhibit activation of pS6 in T cells. 27 We hypothesized that high PD-1 expression and the concomitant high expression of SH2 domain-containing tyrosine phosphatase-2 (SHP-2) 27 could interfere with the putative enhancement of TCR signaling by Tim-3, leading to suppression of T cell activation, as a mechanism of crosstalk between PD-1 and Tim-3. To test this hypothesis, we stimulated sorted TIL subsets from HNSCC patients with anti-CD3/CD28 beads for 48 h and performed intracellular flow cytometry to quantify pS6, as a readout of TCR and Tim-3 signaling.…”

Innate immunity in diabetes and diabetic nephropathy

“…Interestingly, total loss of TLRs can also impair the innate immune system and enhance inflammation. An active immune system has the potential to prevent the development and recurrence of cancer by immunosurveillance, but the tumor microenvironment can cause profound immune suppression and exhaustion 172 . TLR agonists activate both the innate and adaptive immune system and exert antiviral and antitumor activities.…”