Immune checkpoint receptors in cancer: redundant by design?

- Expression patterns of ICRs on immune cells are different.
- Different ICRs utilize different signaling pathways to escape immune attack.
- Different ICRs functions in different stages and sites.
- Co-blockade of different ICRs shows synergistic effects on anti-tumor immunity.

Co-inhibitory receptors expressed on activated immune cells function to regulate T cell tolerance to self-antigens, also serving by tumor cells to escape from eradication by the host immune system. Therefore, blockade of immune checkpoint receptors (ICR) has become a promising immunotherapeutic strategy for treatment of a wide variety of cancers. However, blockade of one of the immune checkpoint receptors alone is often not sufficiently effective; co-blockade shows synergic effects in reversing immunosuppression. In this article, we summarize the expression patterns, mechanisms of action of different ICRs as well as the stages and sites they function in, and discuss how they execute non-redundant suppressive effects in anti-tumor immunity.