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Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: breakthroughs or backups

Abstract

Although immunotherapeutics targeting the inhibitory receptors (IRs) CTLA-4, PD-1 or PD-L1 have made substantial clinical progress in cancer, a considerable proportion of patients remain unresponsive to treatment. Targeting novel IR–ligand pathways in combination with current immunotherapies may improve clinical outcomes. New clinical immunotherapeutics target T cell–expressed IRs (LAG-3, TIM-3 and TIGIT) as well as inhibitory ligands in the B7 family (B7-H3, B7-H4 and B7-H5), although many of these targets have complex biologies and unclear mechanisms of action. With only modest clinical success in targeting these IRs, current immunotherapeutic design may not be optimal. This Review covers the biology of targeting novel IR–ligand pathways and the current clinical status of their immunotherapeutics, either as monotherapy or in combination with antibody to PD-1 or to its ligand PD-L1. Further understanding of the basic biology of these targets is imperative to the development of effective cancer immunotherapies.

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Fig. 1: LAG-3–ligand interactions and current targeting strategies in the clinic.
Fig. 2: TIM-3–ligand interactions and current targeting strategies in the clinic.
Fig. 3: Complex interactions within the PVR family and current targeting strategies in the clinic.
Fig. 4: Members of the B7 family and targeting strategies in the clinic.

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Acknowledgements

The authors thank C. Workman, A. Somasundaram, D. Zandberg and J. Luke for comments. Supported by the US National Institutes of Health (P01 AI108545, R01 CA203689, and R01 AI144422 to D.A.A.V.) and an NCI Comprehensive Cancer Center Support CORE grant (CA047904 to D.A.A.V.).

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Correspondence to Dario A. A. Vignali.

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D.A.A.V. has submitted patents covering LAG-3 that are licensed or pending and is entitled to a share in net income generated from licensing of these patent rights for commercial development.

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Andrews, L.P., Yano, H. & Vignali, D.A.A. Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: breakthroughs or backups. Nat Immunol 20, 1425–1434 (2019). https://doi.org/10.1038/s41590-019-0512-0

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