TIM-3 blockade combined with bispecific antibody MT110 enhances the anti-tumor effect of γδ T cells.

Abstract

As ideal cells that can be used for adoptive cell therapy, γδ T cells are a group of homogeneous cells with high proliferative and tumor killing ability. However, γδ T cells are apt to apoptosis and show decreased cytotoxicity under persistent stimulation in vitro and cannot aggregate at tumor sites efficiently in vivo, both of which are two main obstacles to tumor adoptive immunotherapy. In this study, we found that the immune checkpoint T-cell immunoglobulin domain and mucin domain 3 (TIM-3) were up-regulated significantly on γδ T cells during their ex vivo expansion and this up-regulation contributed to the dysfunction of γδ T cells. Although the killing ability of γδ T cells against breast cancer cells which exhibited a high level of epithelial cell adhesion molecule (EpCAM) was enhanced, the level of TIM-3 on γδ T cells was also further up-regulated under the application of the bispecific antibody MT110 (anti-CD3 × anti-EpCAM) which can redirect T cells to target cells. Besides, these γδ T cells with up-regulated TIM-3 exhibited an increased susceptibility to apoptosis. By reinvigorating dysfunctional γδ T cells and promoting them to accumulate at tumor sites, the combined use of TIM-3 inhibitor and MT110 could further enhance the anti-tumor effect of the adoptively transfused γδ T cells. These results may have clinical implications for the design of new translational anti-tumor regimens aimed at combining checkpoint blockade and immune cell redirection.

• Authors: Qingming Guo, Peng Zhao, Zhen Zhang, Jinyu Zhang, Zheng Zhang, Yanan Hua, Bin Han, Ning Li, Xiaowen Zhao, Lin Hou
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 69 Issue 12 Pg. 2571-2587 (Dec 2020) ISSN: 1432-0851 [Electronic] Germany
• PMID: 32588076 (Publication Type: Journal Article)

Chemical References

• EPCAM protein, human
• Epithelial Cell Adhesion Molecule
• HAVCR2 protein, human
• Hepatitis A Virus Cellular Receptor 2
• MT110 monoclonal antibody
• Single-Chain Antibodies

Topics

• Adult
• Animals
• Apoptosis (drug effects)
• Breast Neoplasms (blood, immunology, pathology, therapy)
• Cells, Cultured
• Coculture Techniques
• Combined Modality Therapy (methods)
• Epithelial Cell Adhesion Molecule (metabolism)
• Female
• Healthy Volunteers
• Hepatitis A Virus Cellular Receptor 2 (antagonists & inhibitors, metabolism)
• Humans
• Immunotherapy, Adoptive (methods)
• Intraepithelial Lymphocytes (drug effects, immunology, metabolism, transplantation)
• Mice
• Middle Aged
• Primary Cell Culture
• Single-Chain Antibodies (pharmacology, therapeutic use)
• Up-Regulation
• Xenograft Model Antitumor Assays