ABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
PD-1 is a target of cancer immunotherapy but responses are limited to a fraction of patients. Identifying patients with T cells subjected to PD-1-mediated inhibition will allow selection of suitable candidates for PD-1-blocking therapy and will improve the therapeutic success. We sought to develop an approach to detect PD-1-mediated inhibitory signaling. The cytoplasmic tail of PD-1 contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) encompassing Y223 and an immunoreceptor tyrosine-based switch motif (ITSM) encompassing Y248, which is indispensable for interaction of SHP-2 and delivery of PD-1 inhibitory function. We generated an antibody specific for phosphorylated PD-1-Y248 and examined PD-1pY248+ (pPD-1) expression in human T cells. pPD-1 was upregulated by TCR/CD3 + CD28 stimulation and simultaneous PD-1 ligation. pPD-1+CD8+ T cells were identified in human peripheral blood and had impaired effector function. pPD-1+ T cells were also detected in tumor-draining lymph nodes of tumor bearing mice and in biopsies of patients with glioblastoma multiform. Detection of pPD-1+ T cells might serve as a biomarker for identification of T cells subjected to PD-1-mediated immunosuppression.
Subject(s)
CD8-Positive T-Lymphocytes/metabolism , Immunoreceptor Tyrosine-Based Inhibition Motif/physiology , Programmed Cell Death 1 Receptor/metabolism , Animals , Antigens, CD/metabolism , Apoptosis/immunology , Apoptosis Regulatory Proteins/metabolism , Biomarkers/blood , CD28 Antigens/metabolism , Female , Glioblastoma/genetics , Glioblastoma/metabolism , Humans , Immunoreceptor Tyrosine-Based Inhibition Motif/genetics , Killer Cells, Natural/immunology , Male , Mice , Mice, Inbred C57BL , Phosphorylation , Primary Cell Culture , Programmed Cell Death 1 Receptor/genetics , Receptors, Immunologic/metabolism , Signal Transduction/immunology , T-Lymphocytes/metabolism , Tyrosine/metabolismABSTRACT
There has been significant progress in utilizing our immune system against cancer, mainly by checkpoint blockade and T cell-mediated therapies. The field of cancer immunotherapy is growing rapidly but durable clinical benefits occur only in a small subset of responding patients. It is currently recognized that cancer creates a suppressive metabolic microenvironment, which contributes to ineffective immune function. Metabolism is a common cellular feature, and although there has been significant progress in understanding the detrimental role of metabolic changes of the tumor microenvironment (TEM) in immune cells, there is still much to be learned regarding unique targetable pathways. Elucidation of cancer and immune cell metabolic profiles is critical for identifying mechanisms that regulate metabolic reprogramming within the TEM. Metabolic targets that mediate immunosuppression and are fundamental in sustaining tumor growth can be exploited therapeutically for the development of approaches to increase the efficacy of immunotherapies. Here, we will highlight the importance of metabolism on the function of tumor-associated immune cells and will address the role of key metabolic determinants that might be targets of therapeutic intervention for improvement of tumor immunotherapies.
