Bispecific anti-CD3 x anti-B7-H3 antibody mediates T cell cytotoxic ability to human melanoma in vitro and in vivo
- 257 Downloads
Inhibition of the B7-H3 immune checkpoint is reported to limit the tumor growth of B7-H3+ tumors. In this study, we demonstrated B7-H3 expression in human melanoma cells, including a primary culture and several cell lines. Furthermore, we investigated whether B7-H3 could serve as a target for T cell-mediated immunotherapy against melanoma. The cytotoxic capacity of activated T cells (ATCs) armed with an anti-CD3 x anti-B7-H3 bispecific antibody (B7-H3Bi-Ab) to melanoma cells was measured using a bioluminescent signal through a luciferase reporter on tumor cells. In contrast to unarmed ATCs, B7-H3Bi-Ab-armed ATCs exhibited increased cytotoxicity against melanoma cells at effector/target ratios from 1:1 to 20:1. Moreover, B7-H3Bi-Ab-armed ATCs secreted more interferin-gamma (IFN-γ), accompanied by higher levels of activating marker CD69 and CD25 expression. Infusion of B7-H3Bi-Ab-armed ATCs suppressed melanoma growth in a xenograft mouse model. Taken together, our results indicate that B7-H3Bi-Ab-armed ATCs may be a promising approach to immunotherapy for melanoma patients.
KeywordsMelanoma B7-H3 Bispecific antibody Immunotherapy
This work is funded by grants from the National Nature Science Foundation of China (No.31400754) and Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20150701).
Compliance with ethical standards
Conflicts of interest
Juan Ma, Tengfei Shang, Pan Ma, Xin Sun, Jin Zhao, Ximing Sun, and Man Zhang declare that they have no conflicts of interest.
All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee. The animal study complied with the Guide for the Care and Use of Laboratory Animals of the Ministry of Health, and the protocol was approved by the Ethics Committee of Beijing Shijitan Hospital of Capital Medical University.
Informed consent was obtained from all individual participants included in the study.
- 2.Dillman RO, CornforthAN DC, McClay EF, Amatruda TT, de Leon C, Ellis RE, Mayorga C, Carbonell D, Cubellis JM (2012) Tumor stem cell antigens as consolidative active specific immunotherapy: a randomized phase II trial of dendritic cells versus tumor cells in patients with metastatic melanoma. J Immunother 35(8):641–649CrossRefGoogle Scholar
- 4.Larkin J, Chiarion-Sileni V, Gonzaler R, Grob JJ, Cowey CL, Lao CD, Schadedof D, Dummer R, Smylie M, Rutkowki P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horek C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34CrossRefGoogle Scholar
- 9.Castellanos JR, Purvis IJ, Labak CM, Guda MR, Tsung AJ, Velpula KK, Asuthkar S (2017) B7-H3 role in the immune landscape of cancer. Am J Clin Exp Immunol 6(4):66–75Google Scholar
- 13.Lee YH, Martin-Orozco N, Zheng P, Li J, Zhang P, Tan H, Park HJ, Jeong M, Chang SH, Kim BS, Xiong W, Zang W, Guo L, Liu Y, Dong ZJ, Overwijk WW, Hwu P, Yi Q, Kwak L, Yang Z, Mak TW, Li W, Radvanyi LG, Ni L, Liu D, Dong C (2017) Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function. Cell Res 27(8):1034–1045CrossRefGoogle Scholar
- 14.Loo D, Alderson RF, Chen FZ, Huang L, Zhang W, Gorlatov S, Burke S, Ciccarone V, Li H, Yang Y, Son T, Chen Y, Easton AN, Li JC, Rillema JR, Licea M, Fieger C, Liang TW, Mather JP, Koenig S, Stewart SJ, Johnson S, Bonvini E, Moore PA (2012) Development of an Fc-enhanced anti–B7-H3 monoclonal antibody with potent antitumor activity. Clin Cancer Res 18(14):3834–3845CrossRefGoogle Scholar
- 18.Ma J, Ma P, Zhao C, Xue X, Han H, Liu C, Tao H, Xiu W, Cai J, Zhang M (2016) B7-H3 as a promising target for cytotoxicity T cell in human cancer therapy. Oncotarget 7(20):29480–29491Google Scholar
- 24.Tiffen JC, Bailey CG, Ng C, Rasko JE, Holst J (2010) Luciferase expression and bioluminescence does not affect tumor cell growth in vitro or in vivo. MolCancer 9:299Google Scholar