Bispecific antibodies enhance tumor-infiltrating T cell cytotoxicity against autologous HER-2-expressing high-grade ovarian tumors

J Leukoc Biol. 2020 Jun;107(6):1081-1095. doi: 10.1002/JLB.5MA1119-265R. Epub 2019 Dec 13.


Epithelial ovarian cancer displays the highest mortality of all gynecological tumors. A relapse of the disease even after successful surgical treatment is a significant problem. Resistance against the current platinum-based chemotherapeutic standard regime requires a detailed ex vivo immune profiling of tumor-infiltrating cells and the development of new therapeutic strategies. In this study, we phenotypically and functionally characterize tumor cells and autologous tumor-derived αβ and γδ T lymphocyte subsets. Tumor-infiltrating (TIL) and tumor-ascites lymphocytes (TAL) were ex vivo isolated out of tumor tissue and ascites, respectively, from high-grade ovarian carcinoma patients (FIGO-stage IIIa-IV). We observed an increased γδ T cell percentage in ascites compared to tumor-tissue and blood of these patients, whereas CD8+ αβ T cells were increased within TAL and TIL. The number of Vδ1 and non-Vδ1/Vδ2-expressing γδ T cells was increased in the ascites and in the tumor tissue compared to the blood of the same donors. Commonly in PBL, the Vγ9 chain of the γδ T cell receptor is usually associated exclusively with the Vδ2 chain. Interestingly, we detected Vδ1 and non-Vδ1/Vδ2 T cells co-expressing Vγ9, which is so far not described for TAL and TIL. Importantly, our data demonstrated an expression of human epidermal growth factor receptor (HER)-2 on high-grade ovarian tumors, which can serve as an efficient tumor antigen to target CD3 TIL or selectively Vγ9-expressing γδ T cells by bispecific antibodies (bsAbs) to ovarian cancer cells. Our bsAbs efficiently enhance cytotoxicity of TIL and TAL against autologous HER-2-expressing ovarian cells.

Keywords: HER-2; T cell subsets; bispecific antibody; cisplatin; human γδ T cells; ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Bispecific / pharmacology*
  • Antineoplastic Agents, Immunological / pharmacology*
  • Ascites / genetics
  • Ascites / immunology
  • Ascites / pathology
  • Ascites / surgery
  • CD3 Complex / genetics
  • CD3 Complex / immunology
  • Carcinoma, Ovarian Epithelial / genetics
  • Carcinoma, Ovarian Epithelial / immunology*
  • Carcinoma, Ovarian Epithelial / pathology
  • Carcinoma, Ovarian Epithelial / surgery
  • Coculture Techniques
  • Cytotoxicity, Immunologic / drug effects
  • Female
  • Gene Expression
  • Humans
  • Lymphocyte Count
  • Lymphocytes, Tumor-Infiltrating / drug effects*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Middle Aged
  • Neoplasm Grading
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / immunology*
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / surgery
  • Primary Cell Culture
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-2 / immunology
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / immunology
  • T-Lymphocytes, Cytotoxic / drug effects*
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / pathology


  • Antibodies, Bispecific
  • Antineoplastic Agents, Immunological
  • CD3 Complex
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Antigen, T-Cell, gamma-delta
  • ERBB2 protein, human
  • Receptor, ErbB-2