Strength of PD-1 signaling differentially affects T-cell effector functions

Abstract

High surface expression of programmed death 1 (PD-1) is associated with T-cell exhaustion; however, the relationship between PD-1 expression and T-cell dysfunction has not been delineated. We developed a model to study PD-1 signaling in primary human T cells to study how PD-1 expression affected T-cell function. By determining the number of T-cell receptor/peptide-MHC complexes needed to initiate a Ca 2+ flux, we found that PD-1 ligation dramatically shifts the dose-response curve, making T cells much less sensitive to T-cell receptor-generated signals. Importantly, other T-cell functions were differentially sensitive to PD-1 expression. We observed that high levels of PD-1 expression were required to inhibit macrophage inflammatory protein 1 beta production, lower levels were required to block cytotoxicity and IFN-γ production, and very low levels of PD-1 expression could inhibit TNF-α and IL-2 production as well as T-cell expansion. These findings provide insight into the role of PD-1 expression in enforcing T-cell exhaustion and the therapeutic potential of PD-1 blockade.

Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma

“…It has been described that these cells are still functional, able to secrete interferon (IFN)-g, resulting in activation of other immune cells that play a role in the antitumor response. 26 We observed PD-1 expression on tumor cells in unpretreated but not in pretreated samples, which has not been described in other cancer types so far. Since a rather low number of pretreated samples was used in our series, future studies including larger validation cohorts are needed to draw any meaningful conclusions.…”

The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints

“…70 Indeed, the blockade of PD-1 increases the sensitivity of T cells to foreign antigens and increases effector function and cytokine production of both CD4+ and CD8+ T cells in models of both tumor and virally mediated chronic T cell exhaustion. 71,72 PD-1 is thought to tune T cells during the effector, rather than priming, phase of T cell antigen encounter. This likely underlies the lower incidence of off-target, autoimmunelike adverse events associated with anti-PD1 as compared to anti-CTLA-4 therapy.…”

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

“…When PD-1 binds to PD-L1 or PD-L2, T-cell proliferation and cytokine release is inhibited through SHP2, which inactivates ZAP70, a major TCR signaling integrator. T-cell function is differentially affected by the strength of PD-1 signaling [31]. Using the cytokines from tumor-infiltrating lymphocytes expressed into microenvironment, cancer cells express PD-L1 (and sometimes PD-L2) to evade immune surveillance [32].…”