文章：

阻断VLA4可使白血病和骨髓瘤肿瘤细胞在骨髓微环境中对CD3重定向敏感

Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment

原文发布日期：2020-06-01

DOI: 10.1038/s41408-020-0331-4

类型: Article

开放获取: 是

英文摘要：

Redirecting T cells to specifically kill malignant cells has been validated as an effective anti-cancer strategy in the clinic with the approval of blinatumomab for acute lymphoblastic leukemia. However, the immunosuppressive nature of the tumor microenvironment potentially poses a significant hurdle to T cell therapies. In hematological malignancies, the bone marrow (BM) niche is protective to leukemic stem cells and has minimized the efficacy of several anti-cancer drugs. In this study, we investigated the impact of the BM microenvironment on T cell redirection. Using bispecific antibodies targeting specific tumor antigens (CD123 and BCMA) and CD3, we observed that co-culture of acute myeloid leukemia or multiple myeloma cells with BM stromal cells protected tumor cells from bispecific antibody-T cell-mediated lysis in vitro and in vivo. Impaired CD3 redirection cytotoxicity was correlated with reduced T cell effector responses and cell–cell contact with stromal cells was implicated in reducing T cell activation and conferring protection of cancer cells. Finally, blocking the VLA4 adhesion pathway in combination with CD3 redirection reduced the stromal-mediated inhibition of cytotoxicity and T cell activation. Our results lend support to inhibiting VLA4 interactions along with administering CD3 redirection therapeutics as a novel combinatorial regimen for robust anti-cancer responses.
 

摘要翻译： 

将T细胞重定向以特异性杀伤恶性细胞已被临床证实为有效的抗癌策略，贝林妥欧单抗治疗急性淋巴细胞白血病的获批便是例证。然而，肿瘤微环境的免疫抑制特性可能对T细胞疗法构成重大障碍。在血液系统恶性肿瘤中，骨髓微环境对白血病干细胞具有保护作用，并降低多种抗癌药物的疗效。本研究探讨了骨髓微环境对T细胞重定向的影响。通过使用靶向特定肿瘤抗原（CD123和BCMA）与CD3的双特异性抗体，我们观察到在体外和体内实验中，将急性髓系白血病或多发性骨髓瘤细胞与骨髓基质细胞共培养时，肿瘤细胞可免受双特异性抗体-T细胞介导的裂解作用。CD3重定向细胞毒性受损与T细胞效应反应减弱相关，且与基质细胞的细胞间接触会降低T细胞活化并赋予癌细胞保护性。最终，阻断VLA4粘附通路联合CD3重定向治疗可减轻基质介导的细胞毒性和T细胞活化抑制。我们的研究结果支持将抑制VLA4相互作用与CD3重定向疗法联合应用，作为实现强效抗癌反应的新型组合方案。

原文链接：

Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment