New frontiers in immune checkpoint B7-H3 (CD276) research and drug development

Abstract

B7-H3 (CD276), a member of the B7 family of proteins, is a key player in cancer progression. This immune checkpoint molecule is selectively expressed in both tumor cells and immune cells within the tumor microenvironment. In addition to its immune checkpoint function, B7-H3 has been linked to tumor cell proliferation, metastasis, and therapeutic resistance. Furthermore, its drastic difference in protein expression levels between normal and tumor tissues suggests that targeting B7-H3 with drugs would lead to cancer-specific toxicity, minimizing harm to healthy cells. These properties make B7-H3 a promising target for cancer therapy.Recently, important advances in B7-H3 research and drug development have been reported, and these new findings, including its involvement in cellular metabolic reprograming, cancer stem cell enrichment, senescence and obesity, have expanded our knowledge and understanding of this molecule, which is important in guiding future strategies for targeting B7-H3. In this review, we briefly discuss the biology and function of B7-H3 in cancer development. We emphasize more on the latest findings and their underlying mechanisms to reflect the new advances in B7-H3 research. In addition, we discuss the new improvements of B-H3 inhibitors in cancer drug development.

Keywords: B7-H3; CD276; Cancer; Drug Development; Immunotherapy.

Fig. 1

Structure of B7-H3 Protein. The dominant form of human B7-H3 is 4IgB7-H3. It includes two identical pairs of IgV-like and IgC-like domains (A), and mouse B7-H3 is 2IgB7-H3, it includes a single pair of IgV-like and IgC-like domains (B)

Fig. 2

Human B7-H3 expression levels in different tissues. Human B7-H3 mRNA expression(A) and protein expression(B) level across human tissues (Source: https://www.proteinatlas.org)

Fig. 3

A diagram of the interaction of cancer cell expressed immune checkpoint B7-H3 with immune cells

Fig. 4

Summary of the molecular mechanisms of the tumorigenic effects of B7-H3. B7-H3 expressed on cell membrane triggers different signaling cascades to activate downstream molecules that contribute to the malignant behaviors of cancer cells

Fig. 5

B7-H3 plays an important role in adipocyte progenitor cell differentiation, lipid oxidation, and obesity. Mature adipose cells derived from adipose progenitors lacking B7-H3 stores more fat and lacks of B7-H3, which increases the risk of obesity and metabolic syndrome in the mouse model

Fig. 6

Cancer immunotherapeutic approaches targeting B7-H3. Anti-B7-H3 approaches using different mechanisms including monoclonal antibodies (mAbs), antibody-dependent cell mediated cytotoxicity (ADCC), CAR-T therapy, and Antibody Drug Conjugate (ADC) have been explored