B7 homolog 3 in pancreatic cancer

Abstract

Despite advances in cancer treatment, pancreatic cancer (PC) remains a disease with high mortality rates and poor survival outcomes. The B7 homolog 3 (B7-H3) checkpoint molecule is overexpressed among many malignant tumors, including PC, with low or absent expression in healthy tissues. By modulating various immunological and nonimmunological molecular mechanisms, B7-H3 may influence the progression of PC. However, the impact of B7-H3 on the survival of patients with PC remains a subject of debate. Still, most available scientific data recognize this molecule as a suppressive factor to antitumor immunity in PC. Furthermore, it has been demonstrated that B7-H3 stimulates the migration, invasion, and metastasis of PC cells, and enhances resistance to chemotherapy. In preclinical models of PC, B7-H3-targeting monoclonal antibodies have exerted profound antitumor effects by increasing natural killer cell-mediated antibody-dependent cellular cytotoxicity and delivering radioisotopes and cytotoxic drugs to the tumor site. Finally, PC treatment with B7-H3-targeting antibody-drug conjugates and chimeric antigen receptor T cells is being tested in clinical studies. This review provides a comprehensive analysis of all PC-related studies in the context of B7-H3 and points to deficiencies in the current data that should be overcome by future research.

Keywords: B7 homolog 3; Immunotherapy; Pancreatic cancer; Prognosis; Signaling pathways.

Figure 1

B7 homolog 3. A: Regulation of B7 homolog 3 (B7-H3) expression and its immunological and nonimmunological tumor-promoting molecular mechanisms; B: Role of B7-H3 in T cell activation. Although some studies recognize B7-H3 as a costimulatory molecule, most available data evidence its coinhibitory role. The B7-H3 receptor(s) is still unknown. Three possible receptors have been suggested to date, namely triggering receptor expressed on myeloid cells-like transcript 2 possibly conducting costimulatory signal, and interleukin 20 receptor subunit alpha, and phospholipase A2 receptor 1 possibly conducting coinhibitory signal. Akt: Protein kinase B; APC: Antigen-presenting cell; B7-H3: B7 homolog 3; CD276: Cluster of differentiation 276, chr: Chromosome; HIF-α: Hypoxia-inducible factor 1-alpha; IFN-γ: Interferon-gamma; IgC: Immunoglobulin constant region; IgV: Immunoglobulin variable region; IL-2: Interleukin-2; IL-10: Interleukin-10; IL-13: Interleukin-13; JAK: Janus kinase; MAPK: Mitogen-activated protein kinase, MEK: MAPK kinase; miRNAs: MicroRNAs; MMPs: Matrix metalloproteinases; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor-kappa B; PI3K: Phosphatidylinositol 3-kinase; STAT: Signal transducer and activator of transcription; VEGF: Vascular endothelial growth factor; MHC: Major histocompatibility complex; TCR: T cell receptor. This Figure was partly generated using images from Servier Medical Art, provided by Servier (https://smart.servier.com/smart_image/), licensed under a Creative Commons Attribution 4.0 international license (https://creativecommons.org/licenses/by/4.0/) (Supplementary material).