In this comprehensive review, Pauken et al. provided emerging evidence on the role of the PD-1 pathway in T cell exhaustion and differentiation, the complexity of PD-1 ligands (B7-1/PD-L1 and PD-L2-RGMb-neogenin) and binding patterns (cis and trans), and current developments in PD-1 checkpoint blockade in cancer. The review highlights the regulatory roles of the PD-1 pathway in diverse differentiation stages of αβ T cells, Tregs, NK, and lymphoid cells, and in tumor cells. The promising results from neoadjuvant anti-PD-1/PD-L1 therapy in several cancers were emphasized, and questions about the optimal timing and alternative methods for PD-1 pathway intervention were raised.
Contributed by Shishir Pant
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.
Author Info: (1) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham an
Author Info: (1) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02215, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02215, USA; Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. (4) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA. (5) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02215, USA. Electronic address: gordon_freeman@dfci.harvard.edu.
