PD-1 Blockade–Mediated Rescue of Exhausted T Cells Requires CD28

When the co-inhibitory receptor programmed cell death-1 (PD-1) binds its ligand (PD-L1), PD-1 signaling suppresses T-cell activation. Thus, the PD-1 pathway is a target for cancer immunotherapy. T-cell activation or PD-L1 binding results in PD-1 phosphorylation by the tyrosine kinase LCK and subsequent recruitment of the phosphatase SHP2. PD-1 is typically thought to suppress T-cell receptor (TCR) signaling, but the downstream targets of PD-1–bound effectors have not been well defined. Hui and colleagues found that SHP2 is the main PD-1 effector, and LCK-mediated dual phosphorylation of PD-1 promotes optimal SHP2 recruitment. Mechanistically, SHP2 dephosphorylates PD-1, destabilizing the PD-1–SHP2 complex and relieving inhibitory signaling in the absence of LCK. Further, the T-cell costimulatory receptor CD28 was identified as a major substrate for PD-1–SHP2-mediated dephosphorylation, and CD28 was dephosphorylated to a much greater extent than TCR signaling components. On the cell surface, PD-1 co-localized more strongly with CD28 than TCR, and in T cells PD-1 preferentially targeted CD28 for dephosphorylation over TCR, altogether suggesting that PD-1 suppresses T-cell function via inactivation of CD28 signaling. In a related study, Kamphorst and colleagues investigated the role of the CD28/B7 pathway for the efficacy of PD-1 targeted therapy. CD28 loss prevented PD-1 blockade from promoting exhausted T-cell proliferation. In a mouse model of colon cancer, anti–PD-L1 induced tumor regression in 8 of 9 mice, but CD28/B7-blockade with anti–PD-L1 resulted in tumor progression in 8 of 10 mice, indicating that CD28 costimulation is required for effective therapy with PD-1 blockade. In patients with advanced non–small cell lung cancer (NSCLC), PD-1 therapy increased the number of proliferative activated CD8 T cells in approximately half of patients, and the activated T cells were largely PD-1⁺CD28⁺. Collectively, these studies indicate that CD28 signaling is essential for effector T-cell activation and may predict responses to PD-1 blockade in patients with cancer.

Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, et al. T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition. Science 2017;355:1428–33.

Kamphorst AO, Wieland A, Nasti T, Yang S, Zhang R, Barber DL, et al. Rescue of exhausted CD8 T cells by PD-1–targeted therapies is CD28-dependent. Science 2017;31:1423–7.

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