Le Yi, Gao Hong, Zhu Angie, Felt Kristen, Rodig Scott, Bleday Ronald, Zhu Zhenglun
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Department of Medicine, Tufts Medical Center, Boston, MA, USA.
iScience. 2022 Oct 22;25(11):105426. doi: 10.1016/j.isci.2022.105426. eCollection 2022 Nov 18.
Limited therapeutic efficacy and severe side effects represent the central hurdles facing cancer chemotherapy. Immune suppression within tumor immune microenvironments (TIME) has been implicated in chemoresistance. In this study, using a TIME-enabling model system (TIME-EMS), we demonstrate that the chemotherapeutic agent doxorubicin has cytocidal effects on tumor cells at high dosage but induces changes in the immune landscape of the TIME at low noncytotoxic concentrations via NF-κB-mediated induction of homeobox protein VentX expression in tumor-associated macrophages (TAMs). We demonstrated that VentX-regulated TAMs drastically promote tumor chemosensitivity >10-fold but exert little effect on chemotoxicity to normal cells through activating cytotoxic T lymphocytes in a tumor-specific manner. Supported by the synergy of VentX-regulated TAMs and low-dosage noncytotoxic doxorubicin, our data suggest a cell-death-independent immune mechanism for improving the therapeutic index of chemotherapeutic agents.
有限的治疗效果和严重的副作用是癌症化疗面临的主要障碍。肿瘤免疫微环境（TIME）中的免疫抑制与化疗耐药有关。在本研究中，我们使用了一种能够模拟TIME的模型系统（TIME-EMS），证明化疗药物阿霉素在高剂量时对肿瘤细胞具有杀伤作用，但在低非细胞毒性浓度下，通过NF-κB介导诱导肿瘤相关巨噬细胞（TAM）中同源盒蛋白VentX表达，可诱导TIME免疫格局发生变化。我们证明，VentX调节的TAM可显著提高肿瘤化疗敏感性10倍以上，但通过以肿瘤特异性方式激活细胞毒性T淋巴细胞，对正常细胞的化学毒性影响很小。在VentX调节的TAM与低剂量非细胞毒性阿霉素协同作用的支持下，我们的数据表明存在一种不依赖细胞死亡的免疫机制来提高化疗药物的治疗指数。
