B7-H3 Pathway

Overview of B7-H3

As a newly found member of the B7/CD28 superfamily, B7-H3 (CD276) is an accessory costimulatory molecule that belongs to type I transmembrane protein. Because B7-H3 is overexpressed in several kinds of human cancer cells and correlated with disease deterioration, B7-H3 has recently been identified as a promising candidate target in multiple cancers.

Increasing data suggest that inhibition of B7-H3 may suppress tumor growth, and B7-H3-targeted therapy has shown broad tumoricidal and antimetastatic activity in vivo. Human B7-H3-Ig fusion protein is found to increase the proliferation of both CD4⁺ and CD8⁺ T cells and enhance the cytotoxic T lymphocyte (CTL) activity in vitro, under the condition of an anti-CD3 antibody mimicking the TCR signal.

Fig.1 B7 family members and their receptors. (Yang, 2020).

B7-H3 and Immunotherapy

In a study, scientists constructed an orthotopic colon cancer mice model to study the mechanism of B7-H3 antitumor ability. The results revealed the antitumor effect of B7-H3 on colon adenocarcinoma, which could be regarded as a promising therapy for the treatment of colon cancers.

In another study, scientists demonstrated for the first time that downregulation of B7-H3 reduced cell adhesion to fibronectin by up to 50% and migration and invasion by more than 70% in melanoma and breast cancer cells. B7-H3 downregulation also led to significant inhibition of cell migration and invasion of human prostate cancer cells.

These results strongly suggest that B7-H3 is involved in cancer progression and metastasis beyond modulating tumor immunity.

Fig.2 Expression of B7-H3 in human tissues. (Liu, 2021)

B7-H3 Immunotherapy

An anti-B7-H3 monoclonal antibody (mAb) shows to mediate potent antibody-dependent cellular cytotoxicity (ADCC) against a broad range of tumor types. Anti-B7-H3 therapy has been studied in preclinical or clinical trials for treating refractory B7-H3-expressing tumors such as melanoma and B7-H3-expressing neoplasms, including osteosarcoma and Ewing’s sarcoma.

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References

1. Yang, S.; et al. B7-H3, a checkpoint molecule, as a target for cancer immunotherapy. International journal of biological sciences. 2020, 16(11): 1767-1773.
2. Liu, J.; et al. Targeting B7-H3 via chimeric antigen receptor T cells and bispecific killer cell engagers augments antitumor response of cytotoxic lymphocytes. Journal of Hematology & Oncology. 2021, 14(1).

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