PD-1-mediated inhibition of T cell activation: Mechanisms and strategies for cancer combination immunotherapy

Abstract

The programmed cell death 1 (PD-1) immune checkpoint of co-inhibitory signaling plays crucial roles in controlling the magnitude and duration of T cell activation to limit tissue damage and maintain self-tolerance. Cancer cells hijack the co-inhibitory pathway and escape immune surveillance by overexpressing the PD-1 ligand PD-L1. Immune checkpoint inhibitors, such as PD-1 blocking antibody have been approved for tumor immunotherapy. However, not all patients can benefit from PD-1 monotherapy. Combination immunotherapy based on PD-1 axis blockade substantially improves clinical anti-tumor efficacy. In this review, we briefly summarize the current progress on the mechanisms of PD-1-mediated inhibition of T cell activation and strategies for cancer combination immunotherapy.

Fig. 1

Effects of PD-1 axis in T cells. Upon PD-1 engagement, the ITSM of PD-1 is phosphorylated, subsequently recruiting and activating the SHP-2 within the PD-1 complex. The activated SHP-2 mediates dephosphorylation of TCR proximal signaling molecules, including Lck and ZAP-70, T cell costimulatory receptor CD28, and common cytokine receptor γ chain (γ_c). Activation of the PI3K-AKT and Ras-MEK-ERK pathways are inhibited. CD28⁻and γ_c family cytokine-triggered immune activation is impaired. In contrast, the expression of transcription factor BATF is up-regulated, which subsequently induces transcription of the E3 ubiquitin ligase MARCH5. MARCH5 is recruited to γ_c and mediates its K27-linked polyubiquitination and lysosomal degradation. The imbalanced activation of signaling pathways alters cell-cycle progression, gene transcription and epigenetic programs in T cells, resulting in a net outcome of T cell quiescence and immune suppression.

Fig. 2

Mechanisms for the synergistic effects of PD-1 blockade plus IL-2. In TME, the high activity of PD-1signaling antagonizes γ_c family cytokines-triggered signaling and immune activation (left). PD-1 blockade eliminates the inhibition of γ_c, thereby restoring the responses of CD8⁺ T cells to the γ_c family cytokines and leading to the synergistic effects of combination immunotherapy of PD-1 blockade and IL-2 (middle). Administration of Pitavastatin Calcium (PC) increases the level of γ_c and leads to improved efficacies of cancer immunotherapy by PD-1 blockade plus IL-2 (right).