Emerging concepts in PD-1 checkpoint biology

Abstract

The PD-1 pathway is a cornerstone in immune regulation. While the PD-1 pathway has received considerable attention for its role in contributing to the maintenance of T cell exhaustion in chronic infection and cancer, the PD-1 pathway plays diverse roles in regulating host immunity beyond T cell exhaustion. Here, we discuss emerging concepts in the PD-1 pathway, including (1) the impact of PD-1 inhibitors on diverse T cell differentiation states including effector and memory T cell development during acute infection, as well as T cell exhaustion during chronic infection and cancer, (2) the role of PD-1 in regulating Treg cells, NK cells, and ILCs, and (3) the functions of PD-L1/B7-1 and PD-L2/RGMb/neogenin interactions. We then discuss the emerging use of neoadjuvant PD-1 blockade in the treatment of early-stage cancers and how the timing of PD-1 blockade may improve clinical outcomes. The diverse binding partners of PD-1 and its associated ligands, broad expression patterns of the receptors and ligands, differential impact of PD-1 modulation on cells depending on location and state of differentiation, and timing of PD-1 blockade add additional layers of complexity to the PD-1 pathway, and are important considerations for improving the efficacy and safety of PD-1 pathway therapeutics.

Keywords: Cancer immunotherapy; Immune regulation; Neoadjuvant; PD-1 pathway; T cell exhaustion.

Figure 1:. Dynamic interplay between PD-L1 and B7-1 influences PD-1, CTLA-4, and CD28 signaling.

PD-1 on T cells binds to its ligand PD-L1 on APCs in trans which delivers an inhibitory signal to T cells. Trans interaction of B7-1 (CD80) with CD28 delivers a positive costimulatory signal to T cells, while CTLA-4 can remove B7-1 by transendocytosis and also deliver T cell intrinsic inhibitory signals. PD-L1 can also bind to B7-1 in cis on the same cell surface. When PD-L1 is bound to B7-1 in cis, PD-L1 cannot engage PD-1 so there is less PD-1 signaling. PD-L1 binding to B7-1 disrupts the B7-1 homodimer and reduces avidity to CTLA-4, reducing B7-1 transendocytosis but CD28 signaling is not impacted. The relative levels of PD-L1 and B7-1 will influence the outcome. An excess of PD-L1 would sequester B7-1 in cis on DCs, reducing the removal of B7-1 by CTLA-4, but unbound PD-L1 should be available for a PD-1 immunoinhibitory signal. In situations or on cells where B7-1 is in excess over PD-L1, the sequestration of PD-L1 by B7-1 would reduce the PD-1 signal and the excess B7-1 could homodimerize and be removed by CTLA-4, making CTLA-4 a dominant checkpoint.

Figure 2:. Stages of the Cancer Immunity Cycle where PD-1 Exerts Effects.

In the Cancer Immunity Cycle [210], DCs in the tumor take up tumor antigens and traffic to the tumor draining LN (dLN), where they encounter rare naïve tumor antigen-specific (referred to as tumor-specific) CD8⁺ T cells. If the activation conditions are appropriate, these tumor-specific CD8⁺ T cells will become activated, proliferate and differentiate into effector cells. In the tumor dLN, the PD-1 pathway plays a critical role in regulating initial T cell priming and effector differentiation. Loss of PD-1 signals promotes T cell expansion and effector differentiation within the tumor dLN. Following activation, T cells traffic to the tumor through the blood. Because the blood is a major route of immune cell trafficking, it is useful for assaying anti-tumor T cell responses en route to the tumor. New CD8⁺ T cell clones trafficking from blood to the tumor are associated with better responses to anti-PD-1. In the tumor, the PD-1 pathway inhibits both CD8⁺ T cells and Treg cells. Recruitment of new CD8⁺ T cells from the periphery into the tumor is associated with better responses to PD-1 blockade, and loss of PD-1 signals has a greater impact on the proliferation of progenitor-like exhausted T cells (T_EX) than terminally exhausted T_EX. The outcome of PD-1 blockade is a balance between enhanced CD8⁺ T cell responses and increased Treg suppressive activity, and protective anti-tumor immune responses following PD-1 blockade are often associated with an increased ratio of CD8⁺ T cells to Treg cells numerically. Abbreviations used in the Figure: PD-1 = Programmed Death-1, T_EX = exhausted CD8⁺ T cells, dLN = tumor draining lymph node. This Figure was created with BioRender.com.