B7 homologue 3 as a prognostic biomarker and potential therapeutic target in gastrointestinal tumors

Abstract

The most common digestive system (DS) cancers, including tumors of the gastrointestinal tract (GIT) such as colorectal cancer (CRC), gastric cancer (GC) and esophageal cancer (EC) as well as tumors of DS accessory organs such as pancreatic and liver cancer, are responsible for more than one-third of all cancer-related deaths worldwide, despite the progress that has been achieved in anticancer therapy. Due to these limitations in treatment strategies, oncological research has taken outstanding steps towards a better understanding of cancer cell biological complexity and heterogeneity. These studies led to new molecular target-driven therapeutic approaches. Different in vivo and in vitro studies have revealed significant expression of B7 homologue 3 (B7-H3) among the most common cancers of the GIT, including CRC, GC, and EC, whereas B7-H3 expression in normal healthy tissue of these organs was shown to be absent or minimal. This molecule is able to influence the biological behavior of GIT tumors through the various immunological and nonimmunological molecular mechanisms, and some of them are shown to be the result of B7-H3-related induction of signal transduction pathways, such as Janus kinase 2/signal transducer and activator of transcription 3, phosphatidylinositol 3-kinase/protein kinase B, extracellular signal-regulated kinase, and nuclear factor-κB. B7-H3 exerts an important role in progression, metastasis and resistance to anticancer therapy in these tumors. In addition, the results of many studies suggest that B7-H3 stimulates immune evasion in GIT tumors by suppressing antitumor immune response. Accordingly, it was observed that experimental depletion or inhibition of B7-H3 in gastrointestinal cancers improved antitumor immune response, impaired tumor progression, invasion, angiogenesis, and metastasis and decreased resistance to anticancer therapy. Finally, the high expression of B7-H3 in most common cancers of the GIT was shown to be associated with poor prognosis. In this review, we summarize the established data from different GIT cancer-related studies and suggest that the B7-H3 molecule could be a promising prognostic biomarker and therapeutic target for anticancer immunotherapy in these tumors.

Targeting B7-H3—A Novel Strategy for the Design of Anticancer Agents for Extracranial Pediatric Solid Tumors Treatment

“…B7-H3 (also known as CD276) is a type I transmembrane glycoprotein discovered in 2001 as a homolog of the B7 family molecules [9]. It involves two extremely similar isoforms in humans, 2Ig-B7-H3 and 4Ig-B7-H3, determined by their extracellular domain, which comprises one or two identical pairs of immunoglobulin variable (IgV)-like and an immunoglobulin constant (IgC)-like domains.…”

“…On the other hand, B7-H3 is widely expressed among cancer cells of various adult human malignancies including colorectal cancer, gastric cancer, esophageal cancer [9], pancreatic cancer [25], liver cancer [26], lung cancer [27], breast cancer [28], ovarian cancer [29], prostatic cancer [30], and renal cell carcinoma [31]. Although the expression of this molecule in PSTs is much less examined, the studies verify that B7-H3 is also overexpressed in CNS tumors [14] and extracranial solid tumors of childhood [4,10,11].…”

“…Furthermore, B7-H3 is proven to influence the biological behavior of many types of cancer through various immunological and nonimmunological molecular mechanisms. This molecule impacts the biological functions of immune system cells, including CD8 + T cells, CD4 + T cells, γδ T cells, CD45RO + T cells, macrophages, and NK cells, and plays a pivotal role in regulating the innate and adaptive immune responses [9,[32][33][34]. Although previously recognized as a costimulatory molecule that promotes T cell activation and interferon-gamma (IFN-γ) production [35], the majority of currently available data confirm that B7-H3 exerts coinhibitory effects on T cell responses, which may allow tumor cells to evade immune destruction [9,33,34,36].…”

“…The results of many recent studies reveal that the B7 homolog 3 (B7-H3) checkpoint molecule seems to be an attractive target for immunotherapy in various adult cancers [8,9]. This molecule was also confirmed to be expressed in extracranial PSTs such as NB, RMS, WT, OS, and ES [4,[10][11][12], as well as in childhood CNS tumors [13][14][15], whereas its expression is absent or very low in normal tissues and organs [16].…”

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

“…Anti-B7-H3 antibody-drug conjugate (ADC) exhibited promising antitumor properties in a variety of tumor models without substantial toxicity [ 83 ]. Bispecific anti-B7-H3/CD3 antibody therapies showed some efficacy in B7-H3-expressing PDAC [ 84 , 85 , 86 ]. Ongoing clinical trials are summarized in Table 1 .…”