Clinical blockade of PD1 and LAG3 — potential mechanisms of action

Key Points Negative regulatory receptors, such as PD1 and LAG3, are expressed on 'exhausted' T cells. However, not all cells that express these receptors are exhausted. Therapeutic blockade of the PD1 pathway shows durable clinical responses in patients with melanoma and other types of cancer. The presumed mechanism of action of PD1 blockade is prevention of the interaction between PD1 on tumour-infiltrating T cells and PDL1 expressed on tumour cells. However, PDL1 expression by tumour cells is not an absolute biomarker of clinical response. PD1 has many other functions and pathways that could also be affected by PD1–PDL1 blockade: for example, PD1 and PDL1 are expressed by a variety of cell types in response to a variety of stimuli. PD1 blockade may also perturb other receptor–ligand interactions. Furthermore, 'reverse signalling' can occur through PDL1. The clinical activity of blocking LAG3 is not yet known, but this could potentially induce anti-tumour responses. Triggering of LAG3 on T cells by MHC class II ligands downregulates T cell function, but may also have other immunomodulatory roles. In addition, soluble LAG3 exhibits immune adjuvant activity. Here, two receptors that inhibit T cell functions — programmed cell death protein 1 (PD1) and lymphocyte activation gene 3 protein (LAG3) — are reviewed. Their mechanisms of action are discussed in the context of clinical blockade for cancer therapy and potential biomarkers of the efficacy of therapeutic blockade are proposed. Dysfunctional T cells can render the immune system unable to eliminate infections and cancer. Therapeutic targeting of the surface receptors that inhibit T cell function has begun to show remarkable success in clinical trials. In this Review, we discuss the potential mechanisms of action of the clinical agents that target two of these receptors, programmed cell death protein 1 (PD1) and lymphocyte activation gene 3 protein (LAG3). We also suggest correlative studies that may define the predominant mechanisms of action and identify predictive biomarkers.