Rescue of exhausted CD8 T cells by PD-1–targeted therapies is CD28-dependent

Abstract

Programmed 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 of mice. 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 CD28/B7 pathway in PD-1 therapy of cancer patients.

CD28 family of receptors inter-connect in the regulation of T-cells

“…Both PD-1 and CD28 preferentially co-cluster to provide a mechanism by which these co-receptors interact for de-phosphorylation. Consistent with this, others have shown that PD-1 blockade requires the expression of CD28 for the recovery of exhausted T cell responses [48] . The interplay involving CTLA-4 and PD-1 with CD28 may be indicative of a general theme of interplay between members of the CD28 family in the regulation of T-cell responses.…”

“…CTLA-4) mice depend on CD28 expression [46] . More recently, two new papers have shown that PD-1 operates via inhibition of CD28 signaling [47,48,49] . PD-1 associates with SHP-2 which preferentially dephosphorylates CD28 (Figure 1B).…”

Small-Molecule Inhibition of PD-1 Transcription Is an Effective Alternative to Antibody Blockade in Cancer Therapy

“…PD-1 expression on tumorinfiltrating CD8 þ T cells correlates with impaired effector cell function (2,11), while PD-L1 expression on tumors can facilitate escape from the host immune system (3) and can serve as a prognostic factor (12). Recent evidence indicates that recovery of responses from anti-PD-1 blockade depends on the related coreceptor (13)(14)(15). The nature of the intracellular signaling pathways that regulate PD-1 expression on T cells has been the subject of much interest.…”

The role of the tumour microenvironment in immunotherapy

“…Current checkpoint inhibitor therapies act by reinforcement of pre-existing T cell anti-tumour responses and are therefore most effective in inflamed tumours. In the presence of an active T cell tumour response, IFN-γ produced by T cells and other immune cells upregulate the expression of PD-L1, which counters T cell receptor and CD28-mediated activation signals of T cells (Hui et al 2017, Kamphorst et al 2017. In clinical studies of PD-1 or PD-L1 antagonists, high T cell density and the adaptive increase of PD-L1 expression on tumour and immune cells are often used as features of an active anti-tumour T cell response (Chen & Mellman 2017).…”