Immune checkpoint of B7-H3 in cancer: from immunology to clinical immunotherapy

Abstract

Immunotherapy for cancer is a rapidly developing treatment that modifies the immune system and enhances the antitumor immune response. B7-H3 (CD276), a member of the B7 family that plays an immunoregulatory role in the T cell response, has been highlighted as a novel potential target for cancer immunotherapy. B7-H3 has been shown to play an inhibitory role in T cell activation and proliferation, participate in tumor immune evasion and influence both the immune response and tumor behavior through different signaling pathways. B7-H3 expression has been found to be aberrantly upregulated in many different cancer types, and an association between B7-H3 expression and poor prognosis has been established. Immunotherapy targeting B7-H3 through different approaches has been developing rapidly, and many ongoing clinical trials are exploring the safety and efficacy profiles of these therapies in cancer. In this review, we summarize the emerging research on the function and underlying pathways of B7-H3, the expression and roles of B7-H3 in different cancer types, and the advances in B7-H3-targeted therapy. Considering different tumor microenvironment characteristics and results from preclinical models to clinical practice, the research indicates that B7-H3 is a promising target for future immunotherapy, which might eventually contribute to an improvement in cancer immunotherapy that will benefit patients.

Keywords: B7-H3; Biomarker; Cancer immune checkpoints; Cancer immunotherapy; Tumor microenvironment.

Fig. 1

Current immune checkpoint receptors and their respective ligands. Many immune checkpoints expressed on the surface of T cells, such as PD-1, CTLA-4, LAG-3, TIGIT, VISTA, and TIM-3, bind to their respective ligands on APCs and/or tumor cells, eliciting positive and/or negative activity in the T cell response. TIM-3 also participates in associated signaling through PtdSer, HMGB-1 and Gal-9 in dying tumor cells. Notably, checkpoints such as PD-L1, CD80, CD226, and VISTA (B7-H5) are expressed on both T cells and APC/tumor cells. B7-H3 is also expressed on the surface of both T cells and APC/tumor cells, but its receptors have not been clearly elucidated, which has engendered great enthusiasm in cancer immunology investigators. In this article, we identify TLT-2, IL20RA, and PLA2R1 as three potential receptors for B7-H3. “+” in green indicates the immunostimulatory (positive) signal, and “−” in red indicates the immunosuppressive (negative) signal. PtdSer, phosphatidylserine; HMGB-1, high-mobility group protein B1; Gal-9, galectin-9

Fig. 2

Structures, distributions, interactions and biological functions of B7-H3 and putative receptors. Three proteins have been identified as potential B7-H3 receptors, including TLT-2 (A), IL20RA (B) and PLA2R1 (C). TLT-2 is widely expressed on the surface of myeloid, B and T cells, and its function in specific cell types has been separately studied. TLT-2 plays a proinflammatory role in CD8+ T cells, neutrophils and microglia while reducing the Th1 immune response and blocking Th1 differentiation when activated on monocytes. The effect of B7-H3 binding to TLT-2 on CD8+ T cells is controversial, and the functional interaction between B7-H3 and TLT-2 in other cell types remains unknown (A). Little is known about the specific cell types that express IL20RA and PLA2R1 and their cell type-specific functions. IL20RA activation enhances breast cancer cell stemness and establishes an immunosuppressive TME via the JAK1/STAT3 signaling pathway, while modulation of the TME via the JAK1/STAT3 pathway through IL20RA and IL20RB is still disputed, requiring more robust and direct evidence (B). PLA2R1 has been indicated as a tumor-suppressive regulator that induces breast cancer cell apoptosis and inhibits transformation to renal cell carcinoma (C). Considering the diverse roles of B7-H3 in the TME, other unknown receptors must be reported continuously. Human B7-H3 gene locates in 15q24.1 and has 12 exons encoding 316 amino acids; the structure of B7-H3 (4IgB7-H3 here, the major isoform in humanity) comprises two identical pairs of extracellular lgV-like and IgC-like domains, a transmembrane region and a 45-aa cytoplasmic tail. Seven B7-H family members (B7-H1 to B7-H7) and their receptors expressed on T cells are also displayed, where B7-H3 binds to TLT-2, IL20RA, PLA2R1 and other interesting as yet unknown receptors. “+” in green indicates the immunostimulatory (positive) signal, and “−” in red indicates the immunosuppressive (negative) signal (D). TME, tumor microenvironment

Fig. 3

Interactions of B7-H3 with immune cells and related pathways facilitate B7-H3 function in the microenvironment. The top panel exhibits interactions with immune cells. B7-H3 was originally identified for its effect on promoting the growth of CD4+ T cells and inhibiting the growth of CD8+ T cells. Activated CD4+ T cells induce IFN-γ production and promote the production of IL-12, while IL-2, IL-10, IL-13 and IFN-γ production are suppressed in CD8+ T cells. B7-H3 also negatively regulates the release of IFN-γ and T cell proliferation in B7-H3-deficient mice. B7-H3 suppresses Th1- and Th2-mediated responses, activity and Treg accumulation. IFN-γ and IFN-5 production and Th1-mediated hypersensitivity are inhibited. However, the release of IL-2 and IL-10 is promoted from Th2 cells. B7-H3 enhances M2 macrophage polarization and the release of cytolytic factors from monocytes, which still requires stronger evidence. The cytolytic function of NK cells is curbed. The bottom panel presents distinct pathways to facilitate B7-H3 function. In the TME and related signaling pathways, the roles of B7-H3 are associated with tumor growth, migration, invasion, metastasis and other processes mediated by the PI3K/AKT/mTOR, JAK2/STAT3 and NF-κB signaling pathways and cell metabolism through the TCA cycle. Overall, B7-H3 regulates tumor cell invasion, migration, apoptosis, metabolism and drug response/resistance through classic pathways; B7-H3 also interacts with many types of immune cells in the microenvironment to influence the immune response. TME, tumor microenvironment; TCA cycle, tricarboxylic acid cycle

Fig. 4

Main associations between B7-H3 and CAFs, tumor cells and other TME cells. Activated B7-H3 increases the proliferation, progression and migration of CAFs and inhibits the apoptosis of CAFs. Inhibiting B7-H3 in gastric cancer decreases the expression of IL-6, CXCL12, FGF1 and VEGF and suppresses the migration of CAFs. B7-H3 activation also promotes tumor cell growth and enhances tumor cell metastasis through AKT pathways. B7-H3 modulates cytokine secretion in many types of TME cells, including T cells, endothelial cells and CAFs, and B7-H3 helps to remodel the ECM by activating MMP2/MMP9. TME, tumor microenvironment; CAFs, cancer-associated fibroblasts; MSCs, mesenchymal stromal cells; ECM, extracellular matrix

Fig. 5

Roles of B7-H3 in several specific cancer types. B7-H3 has various roles in brain tumors, lung cancer, breast cancer, melanoma, liver cancer, gastric cancer, colorectal cancer, cervical cancer and prostate cancer by activating different mechanisms. B7-H3 is negatively associated with the prognosis of glioma and ERG-negative prostate cancer and serves as a promising immunotherapy target in brain tumors, lung cancer and melanoma. The boxes show the available characteristics and function of B7-H3 in cancers. Most characteristics are based on evidence from preclinical models, while specific characteristics highlighted in bold are based on evidence from human (clinical) studies/trials. DIPG, diffuse intrinsic pontine glioma; medulloblastoma, pediatric medulloblastoma; ATRTs, atypical teratoid/rhabdoid tumors; GBM, glioblastoma; CAR-T, chimeric antigen receptor-T cells; NSCLC, non-small cell lung cancer; EMT, epithelial–mesenchymal transformation; SCLC, small-cell lung cancer; MDSCs, myeloid-derived suppressor cells; Tregs, regulatory T cells; TME, tumor microenvironment

Fig. 6

Immunology and future clinical immunotherapy of B7-H3. In T cells, OX40 liganded by OX40 L and the CD4/TCR-MHC II-antigen peptide complex elicit the following signals with a number of well-established proinflammatory mediators, such as PI3K, AKT, NFκB and ERK. Through the PI3K/AKT pathway, many downstream signatures are activated, including NFκB, IL-2 production, mTOR activation and Bcl-xl activation. Then, activated NFκB stimulates the release of cytokines and chemokines. The activation of the TGFβ receptor can inhibit the maturation of miR-21 and enhance PDCD4 levels. The translation of the anti-inflammatory cytokine IL-10 is suppressed in this signal, and the level is downregulated. TGFβ1 can participate in the adhesion, migration and invasion of renal cell carcinoma (RCC) cells. Clinical immunotherapy targeting B7-H3 includes blockade of B7-H3 monoclonal antibodies (mAbs), although the ligand is unclear; B7-H3-specific antibody‒drug conjugates (ADCs); B7-H3-specific antibody-dependent cell-mediated cytotoxicity (ADCC); B7-H3 and CD3 bispecific antibodies; engineered chimeric antigen receptor T cells (CAR-T cells); radionucleotides-induced radioimmunotherapy; other combined therapies (combined with PD-L1, PD-L2, etc.)