B7 Family Members in Pancreatic Ductal Adenocarcinoma: Attractive Targets for Cancer Immunotherapy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate of approximately 5-10%. The immune checkpoint blockade represented by PD-1/PD-L1 inhibitors has been effective in a variety of solid tumors but has had little clinical response in pancreatic cancer patients. The unique suppressive immune microenvironment is the primary reason for this outcome, and it is essential to identify key targets to remodel the immune microenvironment. Some B7 family immune checkpoints, particularly PD-L1, PD-L2, B7-H3, B7-H4, VISTA and HHLA2, have been identified as playing a significant role in the control of tumor immune responses. This paper provides a comprehensive overview of the recent research progress of some members of the B7 family in pancreatic cancer, which revealed that they can be involved in tumor progression through immune-dependent and non-immune-dependent pathways, highlighting the mechanisms of their involvement in tumor immune escape and assessing the prospects of their clinical application. Targeting B7 family immune checkpoints is expected to result in novel immunotherapeutic treatments for patients with pancreatic cancer.

Keywords: B7 family; cancer immunotherapy; immune checkpoint; novel targeted immunotherapies; pancreatic ductal adenocarcinoma.

Figure 1

The B7 family members in the TME of PDAC. The B7 family members are widely expressed in the TME of PDAC, and this diagram mainly depicts the expression of these molecules in the TME, briefly describing how these molecules are involved in the interaction between tumor cells and immune cells and emphasizing their major role in the antitumor immune response. The dashed line indicates a major role as an immune suppressor, and the solid line indicates a major role in PDAC as an immune activator.

Figure 2

B7-H3 promotes pancreatic cancer cell growth. B7-H3 can promote the progression of pancreatic cancer cells through multiple pathways, including promoting pancreatic cancer cell invasion and enhancing cell resistance to drugs and apoptosis, independent of its immunological effects.

Figure 3

B7-H4 promotes the progression of pancreatic cancer. B7-H4 can promote the progression of pancreatic cancer cells through multiple pathways, promoting the growth, migration, and invasion of pancreatic cancer cells independent of its immunological effects.

Figure 4

VISTA expression regulation and function in PDAC. VISTA is primarily expressed in tumor-infiltrating immune cells. Hypoxic TME stimulates VISTA expression via upregulation of HIF-1α, while VISTA is a direct downstream target of reactive p53 molecules. Expression of VISTA may be positively correlated with TLR-4. VISTA can act as a receptor and ligand, binding to several cells and substances in the TME. When serving as a receptor, VISTA binds to the ligand in a pH-dependent manner. VISTA attaches to PSGL-1 on T cells at a pH of about 6.0. When the pH rises to about 7.4, VISTA binds selectively to VSIG-3 on tumor cells, blocking the synthesis of chemicals including IL-2, IL-17, and CCL5. As a ligand, VISTA-Ig greatly increased the conversion of naive T cells into Foxp3+ T cells while suppressing the proliferation of CD4/CD8 T cells, lowering IFN-γ, TNF-α and IL-2 production. The connection between VISTA-VISTA-IgV structural domains on the surface of macrophages and apoptotic cells may facilitate the prompt clearance of apoptotic cells.