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Review
. 2022 Dec 16;23(24):16077.
doi: 10.3390/ijms232416077.

B7-H3/CD276 Inhibitors: Is There Room for the Treatment of Metastatic Non-Small Cell Lung Cancer?

Umberto Malapelle  1 , Paola Parente  2 , Francesco Pepe  1 , Martina Concetta Di Micco  3 , Alessandro Russo  4 , Celeste Clemente  2 , Paolo Graziano  2 , Antonio Rossi  5
Affiliations
Review

B7-H3/CD276 Inhibitors: Is There Room for the Treatment of Metastatic Non-Small Cell Lung Cancer?

Umberto Malapelle et al. Int J Mol Sci. .

Abstract

The striking clinical outcomes of antibody-based immunotherapy, through the inhibitors of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and the programmed cell death protein-1 (PD-1) and its ligand (PD-L1) axis, have driven research aimed at identifying further clinically relevant tumor antigens that can serve as targets in solid tumors. B7 homolog 3 protein (B7-H3, also known as CD276) is a member of the B7 family overexpressed in tumor tissues, including non-small cell lung cancer (NSCLC), while showing limited expression in normal tissues, becoming an attractive and promising target for cancer immunotherapy. B7-H3 expression in tumors has been demonstrated to be associated with poor prognosis. In addition to its role in immune modulation, B7-H3 also promotes pro-tumorigenic functions such as tumor migration, invasion, metastases, resistance, and metabolism. In this review, we will provide an overview of this newly characterized immune checkpoint molecule and its development in the management of metastatic NSCLC.

Keywords: B7-H3; CD276; DS-7300; MGC018; NSCLC; enoblituzumab; immunotherapy; obrindatamab.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
B7-H3 non-immune-mediated (box in the lower left corner) and immune-mediated (cartoon) signaling pathways. PI3K/AKT/mTOR and Ras/Raf/MEK/MAPK signaling pathways are involved in promoting the migration, invasion, and epithelial–mesenchymal transition (ETM) of cancer cells. HIF-α pathway is involved in glucose metabolic reprogramming and enhancing neoplastic tumor growth. VEGF signaling pathway is involved in promoting neo-angiogenesis and metastasis. B7-H3 acts as immune co-stimulatory molecule, increasing IFN-γ and IL-12 levels and promoting CD4+ and CD8+ T cells’ proliferation and enhancing cytotoxic T cell activity. Moreover, B7-H3 plays an immune co-inhibitory role, reducing cytokines (IL-2, IL-10, IL-13, and IFN-γ) and inhibiting T cell proliferation and NK cell activity.
Figure 2
Figure 2
Main B7-H3 inhibitors in solid tumors. ADC: antibody–drug conjugates; mAb: monoclonal antibody; Fc: crystallizable region.
See this image and copyright information in PMC

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