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

摘要

As ideal cells that can be used for adoptive cell therapy, gamma delta T cells are a group of homogeneous cells with high proliferative and tumor killing ability. However, gamma delta 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 gamma delta T cells during their ex vivo expansion and this up-regulation contributed to the dysfunction of gamma delta T cells. Although the killing ability of gamma delta 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 gamma delta T cells was also further up-regulated under the application of the bispecific antibody MT110 (anti-CD3 x anti-EpCAM) which can redirect T cells to target cells. Besides, these gamma delta T cells with up-regulated TIM-3 exhibited an increased susceptibility to apoptosis. By reinvigorating dysfunctional gamma delta 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 gamma delta 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.