Rescue of exhausted CD8 T cells by PD-1–targeted therapies is CD28-dependent
Ce dossier présente un ensemble d'articles mettant en évidence l'intérêt de stimuler la voie de signalisation du récepteur CD28 pour améliorer la réponse tumorale aux traitements anti-PD1
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. 1373Programmed cell death–1 (PD-1)–targeted therapies enhance T cell responses and show efficacy in multiple cancers, but the role of costimulatory molecules in this T cell rescue remains elusive. Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive. Taken together, these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for the CD28/B7 pathway in PD-1 therapy of cancer patients.