Identification of c-Met on Tumor Cells as a Novel Receptor for B7-H3 Entails Implications for Cancer Cell Stemness and Targeted Therapy

Abstract

The immune checkpoint molecule B7-H3 is upregulated in many solid tumors, and B7-H3-targeted immunotherapies are in clinical trials. Recently, a growing body of research has highlighted the presence of tumor cell intrinsic while immune cell-independent functions of B7-H3 in tumorigenesis and cancer cell stemness. However, its receptors and mechanisms of action on cancer cells remain poorly understood. Here, we report that c-Met, a canonical oncogenic receptor tyrosine kinase on cancer cells, is identified as a novel binding protein for B7-H3. The binding between c-Met and B7-H3 directly activates the c-Met/STAT3 signaling cascade, promoting cancer cell stemness in both colorectal cancer and glioblastoma-derived tumor cells. More importantly, we evaluated the translational implications of this discovery by screening a high-affinity antibody designed to selectively disrupt the interaction between B7-H3 and c-Met, demonstrating strong anti-tumor activities, surpassing that of the B7-H3-specific antibody lacking the blocking capability. Combination therapy of this newly developed interaction blocking antibody with c-Met inhibitor results in significantly improved therapeutic effects in inhibiting tumor growth. These findings shed light on previously undisclosed interaction of B7-H3 to c-Met on cancer cells, thereby indicating a new mechanism of cancer cell stemness and intervention pathway of molecular targeted therapy.

Keywords

B7-H3 / cancer cell stemness / monoclonal antibody / molecular targeted therapy

References

[1] A. I. Chapoval, J. Ni, J. S. Lau, et al., “B7-H3: A Costimulatory Molecule for T Cell Activation and IFN-Gamma Production,” Nature Immunology 2 (2001): 269-274.

[2] Y.-H. Lee, N. Martin-Orozco, P. Zheng, et al., “Inhibition of the B7-H3 Immune Checkpoint Limits Tumor Growth by Enhancing Cytotoxic Lymphocyte Function,” Cell Research 27 (2017): 1034-1045.

[3] T. Miyamoto, R. Murakami, J. Hamanishi, et al., “B7-H3 Suppresses Antitumor Immunity via the CCL2-CCR2-M2 Macrophage Axis and Contributes to Ovarian Cancer Progression,” Cancer Immunology Research 10 (2022): 56-69.

[4] H.-J. Liu, H. Du, D. Khabibullin, et al., “mTORC1 Upregulates B7-H3/CD276 to Inhibit Antitumor T Cells and Drive Tumor Immune Evasion,” Nature Communications 14 (2023): 1214.

[5] D. Loo, R. F. Alderson, F. Z. Chen, et al., “Development of an Fc-Enhanced Anti-B7-H3 Monoclonal Antibody With Potent Antitumor Activity,” Clinical Cancer Research 18 (2012): 3834-3845.

[6] Z. Zhou, Y. Si, J. Zhang, et al., “A Dual-Payload Antibody-Drug Conjugate Targeting CD276/B7-H3 Elicits Cytotoxicity and Immune Activation in Triple-Negative Breast Cancer,” Cancer Research 84, no. 22 (2024): 3848-3863.

[7] C. Aggarwal, A. Prawira, S. Antonia, et al., “Dual Checkpoint Targeting of B7-H3 and PD-1 With Enoblituzumab and Pembrolizumab in Advanced Solid Tumors: Interim Results From a Multicenter Phase I/II Trial,” Journal for ImmunoTherapy of Cancer 10 (2022): e004424.

[8] Y. Feng, J. Lee, L. Yang, et al., “Engineering CD276/B7-H3-Targeted Antibody-Drug Conjugates With Enhanced Cancer-Eradicating Capability,” Cell Reports 42 (2023): 113503.

[9] N. A. Vitanza, R. Ronsley, M. Choe, et al., “Intracerebroventricular B7-H3-Targeting CAR T Cells for Diffuse Intrinsic Pontine Glioma: A Phase 1 Trial,” Nature Medicine 31, no. 3 (2025): 861-868.

[10] N. Pinto, C. M. Albert, M. R. Taylor, et al., “STRIvE-02: A First-In-Human Phase I Study of Systemically Administered B7-H3 Chimeric Antigen Receptor T Cells for Patients With Relapsed/Refractory Solid Tumors,” JCO 42, no. 35 (2024): 4163-4172.

[11] D. Li, R. Wang, T. Liang, et al., “Camel Nanobody-Based B7-H3 CAR-T Cells Show High Efficacy Against Large Solid Tumours,” Nature Communications 14, no. 1 (2023): 5920.

[12] N. A. Vitanza, A. L. Wilson, W. Huang, et al., “Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety,” Cancer Discovery 13 (2023): 114-131.

[13] C. Wang, Y. Li, L. Jia, et al., “CD276 Expression Enables Squamous Cell Carcinoma Stem Cells to Evade Immune Surveillance,” Cell Stem Cell 28 (2021): 1597-1613.e7.

[14] A. A. Getu, A. Tigabu, M. Zhou, J. Lu, Ø. Fodstad, and M. Tan, “New Frontiers in Immune Checkpoint B7-H3 (CD276) Research and Drug Development,” Molecular Cancer 22 (2023): 43.

[15] S. Seaman, Z. Zhu, S. Saha, et al., “Eradication of Tumors Through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature,” Cancer Cell 31 (2017): 501-515. e8.

[16] T. Shi, Y. Ma, L. Cao, et al., “B7-H3 Promotes Aerobic Glycolysis and Chemoresistance in Colorectal Cancer Cells by Regulating HK2,” Cell death & disease 10 (2019): 308.

[17] C. Birchmeier, W. Birchmeier, and E. Gherardi, “Met, Metastasis, Motility and More,” Nature Reviews Molecular Cell Biology 4 (2003): 915-925.

[18] L. Ricci-Vitiani, D. G. Lombardi, E. Pilozzi, et al., “Identification and Expansion of Human Colon-Cancer-Initiating Cells,” Nature 445 (2007): 111-115.

[19] J. E. Visvader and G. J. Lindeman, “Cancer Stem Cells in Solid Tumours: Accumulating Evidence and Unresolved Questions,” Nature Reviews Cancer 8 (2008): 755-768.

[20] M. Hashiguchi, H. Kobori, P. Ritprajak, Y. Kamimura, H. Kozono, and M. Azuma, “Triggering Receptor Expressed on Myeloid Cell-Like Transcript 2 (TLT-2) Is a Counter-receptor for B7-H3 and Enhances T Cell Responses,” Proceedings National Academy of Science USA 105 (2008): 10495-10500.

[21] B. Husain, S. R. Ramani, E. Chiang, et al., “A Platform for Extracellular Interactome Discovery Identifies Novel Functional Binding Partners for the Immune Receptors B7-H3/CD276 and PVR/CD155,” Molecular & Cellular Proteomics 18 (2019): 2310-2323.

[22] Z. Liu, W. Zhang, J. B. Phillips, et al., “Immunoregulatory Protein B7-H3 Regulates Cancer Stem Cell Enrichment and Drug Resistance Through MVP-Mediated MEK Activation,” Oncogene 38 (2019): 88-102.

[23] H. H. Niemann, V. Jäger, P. J. G. Butler, et al., “Structure of the Human Receptor Tyrosine Kinase Met in Complex With the Listeria Invasion Protein InlB,” Cell 130 (2007): 235-246.

[24] A. Chaudhri, Y. Xiao, A. N. Klee, X. Wang, and B. Zhu, G. J. Freeman, “PD-L1 Binds to B7-1 Only in Cis on the Same Cell Surface,” Cancer Immunology Research 6 (2018): 921-929.

[25] P.-O. Vidalain, “CD40 Signaling in Human Dendritic Cells Is Initiated Within Membrane Rafts,” EMBO Journal 19 (2000): 3304-3313.

[26] K. Flem-Karlsen, Ø. Fodstad, M. Tan, and C. E. Nunes-Xavier, “B7-H3 in Cancer—Beyond Immune Regulation,” Trends in Cancer 4 (2018): 401-404.

[27] A. Drilon, J. W. Clark, J. Weiss, et al., “Antitumor Activity of Crizotinib in Lung Cancers Harboring a MET Exon 14 Alteration,” Nature Medicine 26 (2020): 47-51.

[28] C. Birchmeier and E. Gherardi, “Developmental Roles of HGF/SF and Its Receptor, the c-Met Tyrosine Kinase,” Trends in Cell Biology 8 (1998): 404-410.

[29] L. Liu, W. Zeng, M. A. Wortinger, et al., “LY2875358, a Neutralizing and Internalizing Anti-MET Bivalent Antibody, Inhibits HGF-Dependent and HGF-Independent MET Activation and Tumor Growth,” Clinical Cancer Research 20 (2014): 6059-6070.

[30] F. Kontos, T. Michelakos, T. Kurokawa, et al., “B7-H3: An Attractive Target for Antibody-Based Immunotherapy,” Clinical Cancer Research 27 (2021): 1227-1235.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.