T cell activation is a highly regulated process involving peptide-MHC engagement of the T cell receptor and positive costimulatory signals. Upon activation, coinhibitory 'checkpoints', including ...programmed cell death protein 1 (PD1), become induced to regulate T cells. PD1 has an essential role in balancing protective immunity and immunopathology, homeostasis and tolerance. However, during responses to chronic pathogens and tumours, PD1 expression can limit protective immunity. Recently developed PD1 pathway inhibitors have revolutionized cancer treatment for some patients, but the majority of patients do not show complete responses, and adverse events have been noted. This Review discusses the diverse roles of the PD1 pathway in regulating immune responses and how this knowledge can improve cancer immunotherapy as well as restore and/or maintain tolerance during autoimmunity and transplantation.
Highlights • T cell exhaustion is present in both chronic infections and cancer. • PD-1 regulates T cell exhaustion and PD-1 blockade enhances tumor and viral immunity. • Molecular pathways of ...exhaustion may reveal biomarkers and immunotherapy targets.
Combination therapies are becoming a focal point in cancer immunotherapy. In this issue of Cancer Cell, Johnston and colleagues identify the TIGIT/CD226 pathway, which provides significant interest ...for combination with PD-1 pathway blockade to improve anticancer CD8+ T cell responses, because it acts by a novel mechanism to regulate CD8+ T cell functions within the tumor microenvironment.
Combination therapies are becoming a focal point in cancer immunotherapy. In this issue of Cancer Cell, Johnston and colleagues identify the TIGIT/CD226 pathway, which provides significant interest for combination with PD-1 pathway blockade to improve anticancer CD8+ T cell responses, because it acts by a novel mechanism to regulate CD8+ T cell functions within the tumor microenvironment.
Programmed death‐1 (PD‐1) is a surface receptor critical for the regulation of T cell function during immunity and tolerance. PD‐1 interactions with its ligands PD‐L1 and PD‐L2 inhibit T cell ...effector functions in an antigen‐specific manner. This paper examines the role of PD‐1 in limiting autoreactivity and establishing self‐tolerance and discusses the hypothesis that PD‐1 ligand (PD‐L) expression both spatially and temporally dictates the fate of self‐reactive T cells during the breakdown of peripheral tolerance and development of autoimmunity. We focus our discussion on the role of PD‐1/PD‐L interactions during peripheral tolerance, the differential role for PD‐L1 and PD‐L2 in response to environmental or self‐antigens, and the impact of PD‐1 signaling on dynamic T cell motility and the T cell receptor (TCR) stop signal. Finally, we discuss the potential to selectively target the PD‐1 pathway therapeutically to alter T cell function during autoimmunity.
Emerging concepts in PD-1 checkpoint biology Pauken, Kristen E.; Torchia, James A.; Chaudhri, Apoorvi ...
Seminars in immunology,
February 2021, 2021-02-00, 20210201, Volume:
52
Journal Article
Peer reviewed
Open access
•The PD-1 pathway plays multifaceted roles in regulating immune responses.•PD-1 can modulate effector and memory T cells, Treg cells, NK cells, and ILCs.•PD-1 regulates anti-tumor T cells in the ...draining lymph node as well as in the tumor.•Timing of PD-1 inhibition may be important for durable anti-tumor immunity.•PD-L1/B7-1 and PD-L2/RGMb/neogenin interactions broaden the impact of the pathway.
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.
Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and ...PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.
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•Chronic IFNG promotes epigenomic and transcriptomic features of resistant tumors•IFN-driven PDL1-independent resistance comprises multiple inhibitory pathways•Targeting IFN-driven resistance improves function of distinct exhausted T cell subsets•Blocking tumor IFN signaling can bypass need for combination checkpoint blockade
Prolonged interferon signaling in tumor cells increases resistance to immune checkpoint blockade through multiple inhibitory pathways, and inhibiting this response can bypass the need for multi-agent blockade.
Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for ...identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion.
Oncology has recently undergone a revolutionary change with widespread adoption of immunotherapy for many cancers. Immunotherapy using monoclonal antibodies against checkpoint molecules, including ...programmed death (PD)-1, PD ligand (PD-L)1, and cytotoxic T lymphocyte-associated antigen (CTLA)-4, is effective in a significant subset of patients. However, immune-related adverse events (irAEs) have emerged as frequent complications of checkpoint blockade, likely due to the physiological role of checkpoint pathways in regulating adaptive immunity and preventing autoimmunity. As immunotherapy becomes more common, a better understanding of the etiology of irAEs and ways to limit these events is needed. At the same time, studying these new therapy-related disorders provides an opportunity to better understand naturally occurring human autoimmune and inflammatory disorders, with the potential to improve therapies for cancer and autoimmune diseases.
IrAEs represent a major obstacle for safely administering checkpoint blockade in cancer patients. Developing methods to minimize irAEs while maintaining effective antitumor immunity could make immunotherapy safer for more cancer patients.
Diverse mechanisms likely drive irAEs, which may share varying degrees of similarities and differences with spontaneous autoimmunity.
IrAEs that develop following checkpoint blockade in cancer provide an opportunity to better understand spontaneous autoimmune and inflammatory disorders.
A deeper understanding of why some patients develop irAEs and others do not is needed to determine who is at highest risk for developing life threatening irAEs and to develop biomarkers to identify these individuals.
Improvements in managing, investigating, and reporting on these irAEs are needed to reduce clinical challenges and maximize opportunities to learn from irAEs.
Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about ...mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.
CD8
T cells are critical mediators of cytotoxic effector function in infection, cancer and autoimmunity. In cancer and chronic viral infection, CD8
T cells undergo a progressive loss of cytokine ...production and cytotoxicity, a state termed T cell exhaustion. In autoimmunity, autoreactive CD8
T cells retain the capacity to effectively mediate the destruction of host tissues. Although the clinical outcome differs in each context, CD8
T cells are chronically exposed to antigen in all three. These chronically stimulated CD8
T cells share some common phenotypic features, as well as transcriptional and epigenetic programming, across disease contexts. A better understanding of these CD8
T cell states may reveal novel strategies to augment clearance of chronic viral infection and cancer and to mitigate self-reactivity leading to tissue damage in autoimmunity.
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