The Positive and Negative Immunoregulatory Role of B7 Family: Promising Novel Targets in Gastric Cancer Treatment

Abstract

Gastric cancer (GC), with a heterogeneous nature, is the third leading cause of death worldwide. Over the past few decades, stable reductions in the incidence of GC have been observed. However, due to the poor response to common treatments and late diagnosis, this cancer is still considered one of the lethal cancers. Emerging methods such as immunotherapy with immune checkpoint inhibitors (ICIs) have transformed the landscape of treatment for GC patients. There are presently eleven known members of the B7 family as immune checkpoint molecules: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Gi24, DD1α, Dies1 SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and Ig-like domain-containing receptor 2 (ILDR2). Interaction of the B7 family of immune-regulatory ligands with the corresponding receptors resulted in the induction and inhibition of T cell responses by sending co-stimulatory and co-inhibitory signals, respectively. Manipulation of the signals provided by the B7 family has significant potential in the management of GC.

Microsatellite Instability, Epstein–Barr Virus, and Programmed Cell Death Ligand 1 as Predictive Markers for Immunotherapy in Gastric Cancer

“…Several biomarkers were identified for prediction, such as PD-L1, MSI-H and EBER. Other than these typical biomarkers, other non-typical biomarkers were also investigated, such as the B7 family [ 15 ]. PD-L1 expression was the first potential biomarker identified for predicting the response to ICIs, and tumor proportion score (TPS) was introduced as a prognostic factor in patients with non-small-cell lung cancer receiving pembrolizumab [ 16 ].…”

Expression of Immune Checkpoints in Malignant Tumors: Therapy Targets and Biomarkers for the Gastric Cancer Prognosis

“…PD-1 regulates T-cell activation by interacting with its ligands, programmed death ligand-1 (PD-L1, B7-H1, CD274) and programmed cell death 1 ligand 2 (PD-L2, B7-DC, CD273). The PD-1 is encoded by PDCD1 gene with five exons, while the PD-L1 is encoded by CD274 gene with seven exons [ 3 ]. Interaction of PD-1 with its ligands leads to an inhibitory effect on the activation of T-lymphocytes, an increase in the number of Foxp3+ T-regulatory cells and inducing of apoptosis of CD8+ cytotoxic T-lymphocytes, which allows the tumor to “escape” the immune response [ 9 ].…”

“…Activation of the Hedgehog pathway in GC leads to increased PD-L1 expression and immunotherapy resistance. Improvement of treatment in GC patients through combination drug therapy with inhibition of ICs and Hedgehog pathway is proposed as possible [ 3 ]. PD-L1 is expressed on the surface of T-, B-lymphocytes, macrophages, dendritic cells (DCs), and bone marrow mast cells [ 11 ].…”

“…The CD276 gene is located on chromosome 15. Extracellular domain of CD276 contains two similar pairs of the immunoglobulin V (IgV) and IgC domains due to exon duplication [ 3 ]. Hashiguchi et al reported that binding of CD276 to its receptor TLT-2 increased T-cell proliferation, cytokine production and cytotoxicity, and the use of antibodies against CD276 and TLT-2 significantly suppressed T-cell activation [ 29 ].…”

“…The present work is a based on the literature analysis attempt to answer these questions. Although there are some reviews on ICs and their expression [ 3 , 4 , 5 , 6 ], the topic has not been considered in such context.…”