Second signals for cancer immunotherapy

Recent years have seen renewed appreciation of the critical role played by the prototypic T cell co-stimulatory receptor CD28 in cancer immunotherapy. Inhibition of co-stimulation by direct competition, as exemplified by cytotoxic T-lymphocyte associated protein 4 (CTLA-4) competition with CD28 for B7 ligands, or interference with intracellular signaling, such as that mediated by SHP2 phosphatase recruited to programmed cell death protein-1 (PD-1), provides tumors with a means to avoid elimination by cytotoxic T cells. Reversing this inhibition or providing co-stimulation by alternative means-bispecific antibodies, chimeric antigen receptors, etc-is the mechanistic basis behind the success of many modern cancer immunotherapies. As such, understanding the complexities of T cell co-stimulation and the various receptors driving it has taken on new importance. In this commentary, we highlight recent studies in this space and discuss their contributions to our understanding of T cell co-stimulatory receptors in cancer.