Costimulatory and coinhibitory receptors in anti-tumor immunity

Abstract

Despite the expression of antigens by tumor cells, spontaneous immune-mediated rejection of cancer seems to be a rare event. T-cell receptor engagement by peptide/major histocompatibility complexes constitutes the main signal for the activation of naive T cells but is not sufficient to initiate a productive generation and maintenance of effector cells. Full activation of T cells requires additional signals driven by costimulatory molecules present on activated antigen-presenting cells but rarely on tumors. Following the discovery of B7-1 (CD80), several other costimulatory molecules have been shown to contribute to T-cell activation and have relevance for improving anti-tumor immunity. Moreover, increasing the understanding of coinhibitory receptors has highlighted key additional pathways that can dominantly inhibit anti-tumor T-cell function. Improving positive costimulation, and interfering with negative regulation, continues to represent an attractive immunotherapeutic approach for the treatment of cancer. This review focuses upon those pathways with the highest potential for clinical application in human cancer patients.

Fig. 1. Schematic of positive costimulatory pathways that could regulate specific stages in an anti-tumor immune response

Depicted are representations of the priming phase in secondary lymphoid organs, and the effector phase within the tumor microenvironment. Most costimulatory signals can be envisioned to improve aspects of the immune response in both compartments, to improve productive cross-priming by APCs and to help maintain the desired functional properties of effector cell subsets. Specific receptor/ligand interactions are defined in the lower right section.

Fig. 2. Schematic of coinhibitory pathways that can be active within tumor-draining lymph nodes and the tumor microenvironment

Depicted are representations of the priming phase in secondary lymphoid organs, and the effector phase within the tumor microenvironment, along with key coinhibitory pathways that could dampen anti-tumor T-cell responses at each level. Several inhibitory signals, such as PD-L1/PD-1 interactions, can regulate both the effectiveness of tumor antigen cross-priming and the function of effector cells at tumor sites. Not all pathways are necessarily relevant for each subtype of cancer and do not necessarily coexist in all individual tumors. Specific receptor/ligand interactions are defined in the lower right section.