T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition

By E. Hui, J. Cheung, Jing Zhu, Xiaolei Su, Marcus J. Taylor, H. Wallweber, Dibyendu K. Sasmal, Jun Huang, J. Kim, I. Mellman and 1 more. Science, 2016

1,468 citations recorded by the source corpus.

Immunotherapeutic PD-1–targeted therapies require CD28 to promote cancer cell killing. CD28 is a critical target for PD-1 blockade PD-1–targeted therapies have been a breakthrough for treating certain tumors and can rejuvenate T cells to unleash the anticancer immune response (see the Perspective by Clouthier and Ohashi). It is widely believed that PD-1 suppresses signaling through the T cell receptor (TCR). However, Hui et al. find instead that the TCR costimulatory receptor, CD28, is the primary target of PD-1 signaling. Independently, Kamphorst et al. show that CD28 is required for PD-1 therapies to kill cancer cells efficiently and eliminate chronic viral infections in mice. Lung cancer patients that responded to PD-1 therapy had more CD28+ T cells, which suggests that CD28 may predict treatment response. Science, this issue p. 1428, p. 1423; see also p. 1373 Programmed cell death–1 (PD-1) is a coinhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). By titrating PD-1 signaling in a biochemical reconstitution system, we demonstrate that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1–recruited Shp2 phosphatase. We also show that CD28, but not the TCR, is preferentially dephosphorylated in response to PD-1 activation by PD-L1 in an intact cell system. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti–PD-L1/PD-1 therapy.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/d00d42c06b8b8704818dc4a24c509578653f64d9

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Citations in the corpus

Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018, background): “Among these, CD28 has recently been found to be the primary target (45).”
Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 (2018, neutral): “, 2017), CD28 co-stimulatory signals (Hui et al., 2017; Kamphorst et al., 2017), patient microbiota (Matson et al.”
Rescue of exhausted CD8 T cells by PD-1 targeted therapies is CD28-dependent (2017, background): “In addition, Hui et. al. show that PD-1 directly targets CD28 cytoplasmic tail, with higher affinity than T cell receptor downstream molecules, further emphasizing the interplay between the CD28 and the PD-1 pathway (26).”
T Cell Dysfunction in Cancer (2018, background): “E urope PM C Funders A uthor M anuscripts E urope PM C Funders A uthor M anuscripts PD-1/PD-L1 signaling suppresses T cell functionality via inactivation of CD28 signaling rather than TCR signaling (Hui et al., 2017).”
Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “PD-1 can inhibit T cell function through SHP2-mediated dephosphorylation of CD28 rather than directly inhibiting TCR signaling [24].”
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “(110) showed that PD-1 specifically targets and dephosphorylates CD28, suggesting that PD-1 suppresses T cell activation through direct repression of CD28 signaling.”
Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory (2019, methodology): “It binds the PD-1 receptor on immune T cells, leading to Sh2p-driven dephosphorylation of the T cell receptor and its co-receptor CD28, thereby suppressing antigen-driven activation of T cells (Hui et al., 2017; Yokosuka et al., 2012).”