Interplay between CD28 and PD-1 in T cell immunotherapy

Immune checkpoint therapy targeting the PD-1/PD-L1 axis has revolutionised the treatment of solid tumors. However, T cell exhaustion underpins resistance to current anti-PD-1 therapies, resulting in lower response rates in cancer patients. CD28 is a T cell costimulatory receptor that can influence the PD-1 signalling pathway (and vice versa). CD28 signalling has the potential to counter T cell exhaustion by serving as a potential complementary response to traditional anti-PD-1 therapies. Here we discuss the interplay between PD-1 and CD28 in T cell immunotherapy and additionally how CD28 transcriptionally modulates T cell exhaustion. We also consider clinical attempts at targeting CD28; the challenges faced by past attempts and recent promising developments.