Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway

Abstract

The PD-1 receptor and ligands PD-L1 and PD-L2, members of the CD28 and B7 families, play critical roles in T cell coinhibition and exhaustion. Overexpression of PD-L1 and PD-1 on tumor cells and tumor-infiltrating lymphocytes, respectively, correlates with poor disease outcome in some human cancers. Monoclonal antibodies (mAbs) blockading the PD-1/PD-L1 pathway have been developed for cancer immunotherapy via enhancing T cell functions. Clinical trials with mAbs to PD-1 and PD-L1 have shown impressive response rates in patients, particularly for melanoma, non-small-cell lung cancer, renal cell carcinoma, and bladder cancer. Further studies are needed to dissect mechanisms of variable response rate, to identify biomarkers for clinical response, to develop small molecule inhibitors, and to combine with other therapies.

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

“…The expression and function of PD-1 have been analyzed mainly in normal peripheral T cells and tumor-infiltrating lymphocytes, [56][57][58] whereas only a few studies have been focused on NK cells. In these studies the expression of PD-1 was detected in PB NK cells derived from patients 37,38,59,60 but not from HDs.…”

The tumor microenvironment disarms CD8+ T lymphocyte function via a miR-26a-EZH2 axis

“…5 In established tumors, the TME is complexly composed of tumor cells and various infiltrating cells, the extracellular matrix, metabolites, growth factors, cytokines, and chemokines that they secrete and dysregulated vasculature. 6 Recently, reversal of CTL dysfunction by blocking either PD-1 on the T cell surface or PD-L1 displayed by cells in the TME has shown unprecedented efficacy in the treatment of a broad range of human cancers, including melanoma, 7,8 non-small cell lung carcinoma (NSCLC), 9 bladder carcinoma, 10 and renal carcinoma. 11 These successes clearly demonstrate that alleviating immune checkpoint suppression is an effective way to treat cancer.…”

Local Concentrations of CC-Chemokine-Ligand 18 Correlate with Tumor Size in Non-small Cell Lung Cancer and Are Elevated in Lymph Node-positive Disease

“…In contrast to agents focusing on molecular targets such as the epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK), whose activity is confined to tumors with specific genetic alterations, immunotherapy is effective in various histological subtypes (5)(6)(7)(8).…”