B7-H3 in Brain Malignancies: Immunology and Immunotherapy

Abstract

The immune checkpoint B7-H3 (CD276), a member of the B7 family with immunoregulatory properties, has been identified recently as a novel target for immunotherapy for refractory blood cancers and solid malignant tumors. While research on B7-H3 in brain malignancies is limited, there is growing interest in exploring its therapeutic potential in this context. B7-H3 plays a crucial role in regulating the functions of immune cells, cancer-associated fibroblasts, and endothelial cells within the tumor microenvironment, contributing to the creation of a pro-tumorigenic milieu. This microenvironment promotes uncontrolled cancer cell proliferation, enhanced metabolism, increased cancer stemness, and resistance to standard treatments. Blocking B7-H3 and terminating its immunosuppressive function is expected to improve anti-tumor immune responses and, in turn, ameliorate the progression of tumors. Results from preclinical or observative studies and early-phase trials targeting B7-H3 have revealed promising anti-tumor efficacy and acceptable toxicity in glioblastoma (GBM), diffuse intrinsic pontine glioma (DIPG), medulloblastoma, neuroblastoma, craniopharyngioma, atypical teratoid/rhabdoid tumor, and brain metastases. Ongoing clinical trials are now investigating the use of CAR-T cell therapy and antibody-drug conjugate therapy, either alone or in combination with standard treatments or other therapeutic approaches, targeting B7-H3 in refractory or recurrent GBMs, DIPGs, neuroblastomas, medulloblastomas, ependymomas, and metastatic brain tumors. These trials hold promise for providing effective treatment options for these challenging intracranial malignancies in both adult and pediatric populations.

Keywords: B7-H3; antibody-drug conjugate therapy; brain tumor; cancer immunotherapy; chimeric antigen receptor T cell therapy; tumor microenvironment.

Figure 1

Structure and Expression of B7-H3 (CD276). B7-H3 is encoded by the exons located on chromosome 9 in mice and on chromosome 15 in humans. The molecule consists of a short cytoplasmic tail, a single transmembrane sequence, and extracellular immunoglobulin domains. In mice, the extracellular domain is composed of an N-terminal IgV and a C-terminal IgC, while in humans, the predominant isoform is 4IgB7-H3, which contains two duplicated IgV-IgC domains. B7-H3 expression varies among different brain tumors but is rarely expressed on normal cells. In addition to the membrane-bound form, the soluble form of B7-H3 has also been detected in human plasma.

Figure 2

Ligands for B7 Family Members. Ten members of the B7 family have been identified, including B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. While major receptors for the majority of B7 family molecules have been identified, the putative ligands for B7-H3 have not been clearly elucidated. Four candidates, including TLT-2, IL20RA, PLA2R1, and AAMP, have been proposed as the possible binding receptors for B7-H3 and need further validation.

Figure 3

Immunological and Non-immunological Functions of B7-H3. Functions of B7-H3 in modulating tumorigenesis, sepsis, allograft rejection, autoimmune diseases, and osteogenesis via immunological and non-immunological mechanisms are complex and multifaceted, as investigated in murine models and patients. Further exploration is under way.

Figure 4

Interactions of B7-H3 with the Tumor Microenvironment (TME) and Its Effects on Tumor Cells. Although the functions of B7-H3 in regulating tumor behaviors are complex, the majority of studies suggest that it plays pro-tumorigenic roles in assisting the development and progression of cancers. B7-H3 exerts its effects mainly in two ways: 1) indirectly, via communications with components of the TME, including infiltrated immune cells, aberrant vascular networks, and cancer-associated fibroblasts, and 2) directly, via multiple signaling pathways that regulate cancer cell proliferation, apoptosis, stemness, invasion, migration, metabolism, and treatment responses.

Figure 5

Therapeutic Strategies Targeting B7-H3. Multiple preclinical studies and early-phase clinical trials have been investigating novel strategies targeting B7-H3, including CAR-T therapy, CAR-NK therapy, monoclonal antibody blocking, bispecific antibody therapy, antibody-drug conjugate (ADC) therapy, and combination treatments with anti-B7-H3 therapies. These strategies have demonstrated remarkable anti-tumor efficacy, improved clinical outcomes, and acceptable drug-related toxicity.