B7-H3 in acute myeloid leukemia: From prognostic biomarker to immunotherapeutic target

Abstract

B7-H3 (CD276), an immune checkpoint protein of the B7 family, exhibits significant upregulation in solid tumors and hematologic malignancies, exerting a crucial role in their pathophysiology. The distinct differential expression of B7-H3 between tumors and normal tissues and its multifaceted involvement in tumor pathogenesis position it as a promising therapeutic target for tumors. In the context of acute myeloid leukemia (AML), B7-H3 is prominently overexpressed and closely associated with unfavorable prognoses, yet it has remained understudied. Despite various ongoing clinical trials demonstrating the potential efficacy of immunotherapies targeting B7-H3, the precise underlying mechanisms responsible for B7-H3-mediated proliferation and immune evasion in AML remain enigmatic. In view of this, we comprehensively outline the current research progress concerning B7-H3 in AML, encompassing in-depth discussions on its structural attributes, receptor interactions, expression profiles, and biological significance in normal tissues and AML. Moreover, we delve into the protumor effects of B7-H3 in AML, examine the intricate mechanisms that underlie its function, and discuss the emerging application of B7-H3-targeted therapy in AML treatment. By juxtaposing B7-H3 with other molecules within the B7 family, this review emphasizes the distinctive advantages of B7-H3, not only as a valuable prognostic biomarker but also as a highly promising immunotherapeutic target in AML.

Figure 1

Structural composition (A) and amino acid sequence (B) of B7-H3. B7-H3 is a type I transmembrane protein comprising an ectodomain, a transmembrane domain, and an endodomain. The figure illustrates two isoforms of B7-H3: 4Ig B7-H3, 2Ig B7-H3, and the soluble form (sB7-H3). The amino acid sequence of B7-H3 with each color representing different domains. The functional FG loops of the IgV domain are marked with blue arrows. IgC: Immunoglobulin constant; IgV: Immunoglobulin variable.

Figure 2

Interactions and functions of B7-H3 with putative receptors. Four candidate proteins identified as potential B7-H3 receptors and their possible interactions with B7-H3 are illustrated in the figure. AAMP: Angio-associated migratory cell protein; BM: Bone marrow; CTL: Cytotoxic T lymphocyte; ERR: Estrogen-related receptor; IFN-γ: Interferon-gamma; IL-20RA: Interleukin-20 receptor subunit alpha; JAK: Janus kinase; MDSC: Myeloid-derived suppressor cell; NF-κB: Nuclear factor kappa-B; PARP1: Poly ADP-ribose polymerase; PD-L1: Programmed cell death-ligand 1; PLA2R1: Phospholipase A2 receptor 1; RhoA: Ras homolog family member A; ROS: Reactive oxygen species; STAT: Signal transducer and activator of transcription; Th1: T helper 1 cell; TLT-2: Triggering receptor expressed on myeloid cell-like transcript 2; TME: Tumor microenvironment; VSMC: Vascular smooth muscle cell.

Figure 3

A proposed model for the role of B7-H3 in tumorigenesis. B7-H3 demonstrates a protumor impact by altering tumor biological behavior, maintaining tumor stemness, constructing an immunosuppressive TME by inhibiting the immune response and promoting angiogenesis and ECM remodeling. Overall, B7-H3 has been shown to promote tumor proliferation, infiltration, metastasis, and chemoresistance via various signaling routes. AKT: Protein kinase B; α-SMA: Alpha smooth muscle actin; BAX: B cell lymphoma-associated X-protein; BCL-2: B cell lymphoma 2; BCL-XL: B cell lymphoma extra-large; c-Myc: Myelocytomatosis virus oncogene cellular homolog; CAF: Cancer-associated fibroblast; CSC: Cancer stem cell; CTL: Cytotoxic T lymphocyte; DC: Dendritic cell; ECM: Extracellular matrix; EMT: Epithelial-mesenchymal transition; ENO1: Enolase 1; HIF-1α: Hypoxia inducible factor-1 alpha; IL: Interleukin; JAK: Janus kinase; LDHA: L-lactate dehydrogenase A chain; MEK: Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase; MMP: Matrix metalloproteinase; mTOR: Mammalian target of rapamycin; MVP: Major vault protein; NK: Natural killer; NF-κB: Nuclear factor kappa-B; PI3K: Phosphoinositide 3-kinase; sB7-H3: Soluble B7-H3; Smad: Smooth muscle actin (SMA) and mothers against decapentaplegic(Mad)-related protein; STAT: Signal transducer and activator of transcription; TAM: Tumor-associated macrophage; TME: Tumor microenvironment; Treg: Regulatory T cell; VEGF: Vascular endothelial growth factor.

Figure 4

Immunotherapy strategies targeting B7-H3 in AML. Different strategies targeting B7-H3 for the treatment of solid tumors and hematologic malignancies, including mAbs, BsAbs, TriKEs, ADCs, RIT, and CAR-T cell therapies. ADC: Antibody-drug conjugate; AML: Acute myeloid leukemia; BCL-XL: B cell lymphoma extra-large; BiKE: Bispecific killer-cell engager; BiTE: Bispecific T-cell engager; BsAb: Bispecific antibody; CAR-T: Chimeric antigen receptor T-cell; CD: Cluster of differentiation; mAb: Monoclonal antibody; IL: Interleukin; NK: Natural killer; PD-L1: Programmed cell death-ligand 1; RIT: Radioimmunotherapy; TCR: T-cell receptor; TriKE: Tri-specific killer engager.