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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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References

  1. Bachireddy P, Burkhardt UE, Rajasagi M, Wu CJ (2015) Haematological malignancies: at the forefront of immunotherapeutic innovation. Nat Rev Cancer 15(4):201–215

    Article  CAS  Google Scholar 

  2. Im A, Pavletic SZ (2017) Immunotherapy in hematologic malignancies: past, present, and future. J Hematol Oncol 10(1):94

    Article  Google Scholar 

  3. Shallis RM, Wang R, Davidoff A, Ma X, Zeidan AM (2019) Epidemiology of acute myeloid leukemia: recent progress and enduring challenges. Blood Rev pii: S0268-960X(18): 30139–5. https://doi.org/10.1016/j.blre.2019.04.005

  4. Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D, Dong H, Sica GL, Zhu G, Tamada K, Chen L (2001) B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol 2(3):269–274

    Article  CAS  Google Scholar 

  5. Picarda E, Ohaegbulam KC, Zang X (2016) Molecular pathways: targeting B7-H3 (CD276) for human cancer immunotherapy. Clin Cancer Res 22(14):3425–3431

    Article  CAS  Google Scholar 

  6. Guery T, Roumier C, Berthon C, Renneville A, Preudhomme C, Quesnel B (2015) B7-H3 protein expression in acute myeloid leukemia. Cancer Med 4(12):1879–1883

    Article  CAS  Google Scholar 

  7. Hu Y, Lv X, Wu Y, Xu J, Wang L, Chen W, Zhang W, Li J, Zhang S, Qiu H (2015) Expression of costimulatory molecule B7-H3 and its prognostic implications in human acute leukemia. Hematology 20(4):187–195

    Article  Google Scholar 

  8. Ramsay AG, Clear AJ, Fatah R, Gribben JG (2012) Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood 120(7):1412–1421

    Article  CAS  Google Scholar 

  9. Zhu XW, Wang J, Zhu MX, Wang YF, Yang SY, Ke XY (2019) MicroRNA-506 inhibits the proliferation and invasion of mantle cell lymphoma cells by targeting B7H3. Bioch Biophys Res Commun 508(4):1067–1073

  10. Lin L, Cao L, Liu Y, Wang K, Zhang X, Qin X, Zhao D, Hao J, Chang Y, Huang X, Liu B, Zhang J, Lu J, Ge Q (2018) B7-H3 promotes multiple myeloma cell survival and proliferation by ROS-dependent activation of Src/STAT3 and c-Cbl-mediated degradation of SOCS3. Leukemia. https://doi.org/10.1038/s41375-018-0331-6

  11. 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):1034–1045

    Article  CAS  Google Scholar 

  12. Janakiram M, Shah UA, Liu W, Zhao A, Schoenberg MP, Zang X (2017) The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3. Immunol Rev 276(1):26–39

    Article  CAS  Google Scholar 

  13. Zhang W, Wang J, Wang Y, Dong F, Zhu M, Wan W, Li H, Wu F, Yan X, Ke X (2015) B7-H3 silencing by RNAi inhibits tumor progression and enhances chemosensitivity in U937 cells. Onco Targets Ther 8:1721–1733

    Article  CAS  Google Scholar 

  14. Zhang W, Wang Y, Wang J, Dong F, Zhu M, Wan W, Li H, Wu F, Yan X, Ke X (2015) B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity. Int J Oncol 46(6):2562–2572

    Article  CAS  Google Scholar 

  15. Nagase-Zembutsu A, Hirotani K, Yamato M, Yamaguchi J, Takata T, Yoshida M, Fukuchi K, Yazawa M, Takahashi S, Agatsuma T (2016) Development of DS-5573a: a novel afucosylated mAb directed at B7-H3 with potent antitumor activity. Cancer Sci 107(5):674–681

    Article  CAS  Google Scholar 

  16. Majzner RG, Theruvath JL, Nellan A, Heitzeneder S, Cui Y, Mount CW, Rietberg SP, Linde MH, Xu P, Rota C, Sotillo E, Labanieh L, Lee DW, Orentas RJ, Dimitrov DS, Zhu Z, St Croix B, Delaidelli A, Sekunova A, Bonvini E, Mitra SS, Quezado MM, Majeti R, Monje M, Sorensen PH, Maris JM, Mackall CL (2019) CAR T cells targeting B7-H3, a pan-cancer antigen, demonstrate potent preclinical activity against pediatric solid tumors and brain tumors. Clin Cancer Res 25:2560–2574. https://doi.org/10.1158/1078-0432.CCR-18-0432

    Article  PubMed  Google Scholar 

  17. Hoffman LM, Gore L (2014) Blinatumomab, a bi-specific anti-CD19/CD3 bite((R)) antibody for the treatment of acute lymphoblastic leukemia: perspectives and current pediatric applications. Front Oncol 4:63

    Article  Google Scholar 

  18. Reusch U, Harrington KH, Gudgeon CJ, Fucek I, Ellwanger K, Weichel M, Knackmuss SH, Zhukovsky EA, Fox JA, Kunkel LA, Guenot J, Walter RB (2016) Characterization of CD33/CD3 tetravalent bispecific tandem diabodies (tandAbs) for the treatment of acute myeloid leukemia. Clin Cancer Res 22(23):5829–5838

    Article  CAS  Google Scholar 

  19. Demichelis-Gomez R, Perez-Samano D, Bourlon C (2019) Bispecific antibodies in hematologic malignancies: when, to whom, and how should be best used? Curr Oncol Rep 21(2):17

    Article  Google Scholar 

  20. 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):29480–29491

    PubMed  PubMed Central  Google Scholar 

  21. Ma W, Ma J, Ma P, Lei T, Zhao M, Zhang M (2018) Targeting immunotherapy for bladder cancer using anti-CD3x B7-H3 bispecific antibody. Cancer Med 7(10):5167–5177

    Article  CAS  Google Scholar 

  22. Ma J, Shang T, Ma P, Sun X, Zhao J, Sun X, Zhang M (2019) Bispecific anti-CD3 x anti-B7-H3 antibody mediates T cell cytotoxic ability to human melanoma in vitro and in vivo. Investig New Drugs. https://doi.org/10.1007/s10637-018-00719-7

  23. Ma J, Han H, Liu D, Li W, Feng H, Xue X, Wu X, Niu G, Zhang G, Zhao Y, Liu C, Tao H, Gao B (2013) HER2 as a promising target for cytotoxicity T cells in human melanoma therapy. PLoS One 8(8):e73261

    Article  CAS  Google Scholar 

  24. Yang Y (2015) Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest 125(9):3335–3337

    Article  Google Scholar 

  25. Clynes RA, Desjarlais JR (2019) Redirected T cell cytotoxicity in cancer therapy. Annu Rev Med 70:437–450

    Article  CAS  Google Scholar 

  26. Sathaliyawala T, Kubota M, Yudanin N, Turner D, Camp P, Thome JJ, Bickham KL, Lerner H, Goldstein M, Sykes M, Kato T, Farber DL (2013) Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 38(1):187–197

    Article  CAS  Google Scholar 

  27. Ross SL, Sherman M, McElroy PL, Lofgren JA, Moody G, Baeuerle PA, Coxon A, Arvedson T (2017) Bispecific T cell engager (BiTE(R)) antibody constructs can mediate bystander tumor cell killing. PLoS One 12(8):e0183390

    Article  Google Scholar 

  28. Fatehchand K, McMichael EL, Reader BF, Fang H, Santhanam R, Gautam S, Elavazhagan S, Mehta P, Buteyn NJ, Merchand-Reyes G, Vasu S, Mo X, Benson DM Jr, Blachly JS, Carson WE 3rd, Byrd JC, Butchar JP, Tridandapani S (2016) Interferon-γ promotes antibody-mediated fratricide of acute myeloid leukemia cells. J Biol Chem 291(49):25656–25666

    Article  CAS  Google Scholar 

  29. Sznol M, Chen L (2013) Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer--response. Clin Cancer Res 19(19):5542

    Article  CAS  Google Scholar 

  30. Yamashita T, Tamura H, Satoh C, Shinya E, Takahashi H, Chen L, Kondo A, Tsuji T, Dan K, Ogata K (2009) Functional B7.2 and B7-H2 molecules on myeloma cells are associated with a growth advantage. Clin Cancer Res 15(3):770–777

    Article  CAS  Google Scholar 

  31. Feucht J, Kayser S, Gorodezki D, Hamieh M, Doring M, Blaeschke F, Schleqel P, Bosmuller H, Quintanilla-Fend L, Ebinger M, Lang P, Handgretinger R, Feuchtinger T (2016) T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts. Oncotarget 7(47):76902–76919

    Article  Google Scholar 

  32. Maeda A, Yamamoto K, Yamashita K, Asagoe K, Nohgawa M, Kita K, Iwasaki H, Ueda T, Takahashi A, Sasada M (1998) The expression of co-stimulatory molecules and their relationship to the prognosis of human acute myeloid leukaemia: poor prognosis of B7-2-positive leukaemia. Br J Haematol 102(5):1257–1262

    Article  CAS  Google Scholar 

  33. Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, Lukez AP, Avigan D, Chen YB, McSweeney P, LeBoeuf NR, Rooney MS, Bowden M, Zhou CW, Granter SR, Hornick JL, Rodig SJ, Hirakawa M, Severgnini M, Hodi FS, Wu CJ, Ho VT, Cutler C, Koreth J, Alyea EP, Antin JH, Armand P, Streicher H, Ball ED, Ritz J, Bashey A, Soiffer RJ, Leukemia, Lymphoma Society Blood Cancer Research P (2016) Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med 375 (2):143–153

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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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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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