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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.

Abstract

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.

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Figure 1: Receptors that negatively regulate T cell function.
Figure 2: Mechanisms of action of PD1, PDL1 and PDL2.
Figure 3: The network of receptors and ligands potentially affected by PD1 blockade.
Figure 4: Membrane-bound versus soluble LAG3.

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Acknowledgements

The authors thank O. Chan for her contributions to this article.

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Correspondence to Linh T. Nguyen or Pamela S. Ohashi.

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Glossary

Exhaustion

A state of impaired T cell function that results from chronic exposure to an antigen.

Inhibitory receptors

Receptors that negatively regulate cellular function. They may contain immunoreceptor tyrosine-based inhibition (ITIM) motifs. The absence of such receptors or their inhibition by antagonistic antibodies leads to improved cell function.

Merkel cell

A cell type in the epithelium that is essential for the fine resolution of sensory stimuli; this cell type is malignantly transformed in Merkel cell carcinoma.

Two-photon intravital microscopy

Laser-scanning microscopy that uses near-infrared laser light for the excitation of conventional fluorophores or fluorescent proteins. Owing to the deep tissue penetration of light, the main advantage is the ability to visualize live and intact specimens.

T follicular helper cells

(TFH cells). CD4+ T helper cells that function in providing help for B cell responses, including the formation of germinal centres and differentiation of B cells into antibody-producing plasma cells.

Germinal centre

Located in peripheral lymphoid tissues (for example, the spleen), these structures are sites of B cell proliferation and selection for clones that produce antigen-specific antibodies of higher affinity.

Recombination-activating gene

(RAG). RAG1 and RAG2 are essential for the rearrangement process that generates diversity in T cell receptor and antibody loci. Mice that are deficient for either of these genes fail to produce B cells or T cells owing to a developmental block in the gene rearrangement that is necessary for antigen receptor expression.

Objective responses

Reductions in tumour burden that satisfy the criteria for a complete or partial response.

Trogocytosis

A process in which a cell can acquire portions of the cell membrane and molecules within the membrane from another cell. The term is generally used for immune cells.

Adjuvant

An agent that improves an immune response, generally acting via stimulating antigen-presenting cells.

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Nguyen, L., Ohashi, P. Clinical blockade of PD1 and LAG3 — potential mechanisms of action. Nat Rev Immunol 15, 45–56 (2015). https://doi.org/10.1038/nri3790

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