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T cell cytotoxicity toward hematologic malignancy via B7-H3 targeting

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Summary

T cells are important effectors in anti-tumor immunity, and aberrant expression of B7 family members may contribute to tumor evasion. In this study, we analyzed expression of costimulatory molecules on human hematologic tumor cells and explored whether B7-H3, a member of the B7 superfamily, is an effective target for T cell mediated cytotoxicity toward hematologic malignancy. We investigated the bispecific antibody anti-CD3 × anti-B7-H3 (B7-H3Bi-Ab) for its ability to redirect T cells to target B7-H3 positive hematologic tumors, including Thp-1, K562, Daudi cells and a primary culture. The capacity of T cells armed with B7-H3Bi-Ab to kill hematologic tumors was evaluated by lactate dehydrogenase assay, flow cytometry, ELISA, and luciferase quantitative assay at an effector/target ratio of 5:1. Compared with unarmed T cells, B7-H3Bi-Ab-armed T cells exhibited significant cytotoxicity toward hematological tumor cells. Moreover, B7-H3Bi-Ab-armed T cells secreted more IFN-γ, TNF-α, IL-2, and Granzyme B and expressed higher levels of activating marker CD69 compared to unarmed T cells. In conclusion, B7-H3Bi-Ab enhances the ability of T cells to kill hematologic tumor cells, and B7-H3 may serve as a novel target for immunotherapy against hematologic malignancy.

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Funding

This work is funded by grants from the National Nature Science Foundation of China (No.31400754), Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20150701), and Independent Research Project of China Academy of Chinese Medical Sciences (No.YZ-1713).

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Authors and Affiliations

  1. Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, 10 Tieyi Road, Haidian District, Beijing, 100038, China

    Xin Sun, Zhenkui Gao, Juan Ma & Man Zhang

  2. Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, 100038, China

    Xin Sun, Juan Ma & Man Zhang

  3. Peking University Ninth School of Clinical Medicine, Beijing, 100038, China

    Yang Yu, Zhenkui Gao, Juan Ma & Man Zhang

  4. Department of Hematology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China

    Yang Yu

  5. Department of Gynecology and Obstetrics, China-Japan Friendship Hospital, Capital Medical University, Beijing, 100029, China

    Li Ma

  6. Institute of Basic Theory, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Xin Xue

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  1. Xin Sun
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Correspondence to Juan Ma.

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Conflict of interest

Xin Sun, Yang Yu, Li Ma, Xin Xue, Zhenkui Gao, Juan Ma, and Zhang Man have declared that they have no conflicting interests.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Sun, X., Yu, Y., Ma, L. et al. T cell cytotoxicity toward hematologic malignancy via B7-H3 targeting. Invest New Drugs 38, 722–732 (2020). https://doi.org/10.1007/s10637-019-00819-y

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