Journal Article

Functional differences between PD-1+ and PD-1- CD4+ effector T cells in healthy donors and patients with glioblastoma multiforme

Hernandez, Amanda L., Raddassi, Khadir, Lucca, Liliana E., Lerner, Benjamin A., Gunel, Murat, Coric, Vlad, Lowther, Daniel E., Hafler, David A., Love, J. Christopher, Goods, Brittany A.

2017

Overview

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25-CD127+Foxp3-effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1+CD4+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1+ CD4+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1+TIM-3+ CD4+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1-CD4+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1-CD4+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antibodies / Antibodies, Blocking - therapeutic use / Apoptosis / Bioengineering / Bioinformatics / Biology and Life Sciences / Brain / Brain cancer / Brain tumors / Cancer / Cancer therapies / CD25 antigen / CD4 antigen / CD4-Positive T-Lymphocytes - drug effects / CD4-Positive T-Lymphocytes - metabolism / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - metabolism / Cell death / Cell Proliferation - drug effects / Cell Proliferation - genetics / Chemical engineering / Compartments / Computer Science / Departments / Effector cells / Effectors / Enrichment / Exhaustion / Flow Cytometry / Foxp3 protein / Gene sequencing / Genomes / Glioblastoma / Glioblastoma - immunology / Glioblastoma - metabolism / Glioblastoma multiforme / Healthy Volunteers / Hepatitis A Virus Cellular Receptor 2 - metabolism / Humans / Immune checkpoint inhibitors / Immunology / Immunotherapy / Inhibitors / Interferon / Interferon-gamma - metabolism / Interleukin-2 - therapeutic use / Life Sciences / Ligands / Lymphocytes / Lymphocytes T / Medical research / Medicine / Medicine and Health Sciences / Melanoma / Metabolism / Movement disorders / Neurodegenerative diseases / Neurology / Parkinson's disease / Patients / PD-1 protein / Programmed Cell Death 1 Receptor - metabolism / Proteins / Receptors / Recovery of function / Research and Analysis Methods / Ribonucleic acid / RNA / T cell receptors / Telomere - metabolism / Tumors