Combination of MAPK inhibition with photothermal therapy synergistically augments the anti-tumor efficacy of immune checkpoint blockade
Combination of MAPK inhibition with photothermal therapy synergistically augments the anti-tumor efficacy of immune checkpoint blockade
复制标题
MAPK 抑制与光热疗法的结合可协同增强免疫检查点阻断的抗肿瘤功效。
DOI：
10.1016/j.jconrel.2021.02.020
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发表时间：
2021-03-01
影响因子：
10.8
通讯作者：
Shi, Hubing
中科院分区：
文献类型：
--
作者：
Liu, Xiaowei;Feng, Yanlin;Shi, Hubing
MAPK靶向治疗和免疫检查点阻断相结合是治疗晚期黑色素瘤患者最有前途的方案之一。然而，联合方案的协同疗效在临床试验中仍存在争议。在此，我们报道了MAPK抑制诱导的肿瘤微环境中T细胞抑制是通过HSP27/HSP70的减弱和新抗原提呈的缺乏而介导的。为了解决这一问题，我们设计了一种光热响应型按需可控释药的金纳米系统来携带BRAF抑制剂。该纳米系统可以特异性地输送到肿瘤细胞中，而不是T细胞中，并在激光照射下有效地将光能转化为热能。光热联合靶向治疗可显著促进免疫原性细胞死亡和T细胞浸润。在该方案的基础上，系统地应用PD-1抗体不仅可以抑制局部治疗的肿瘤，还可以通过增强全身免疫相关的抗肿瘤反应来抑制异位肿瘤。更重要的是，三联疗法可以有效地将免疫？感冒？肿瘤变热了吗？一个。综上所述，我们的研究证明了光热-靶向-免疫三联方案在治疗临床上不能切除的多灶性和缺乏T细胞浸润的肿瘤方面具有优势。
The combination of MAPK-targeted therapy and immune checkpoint blockade is one of the most promising regimens for patients with advanced melanoma. However, the synergistic efficacy of the combo regimen is still controversial in clinical trials. Here, we report that MAPK inhibition induced T-cell suppression within tumor microenvironment is mediated by attenuation of HSP27/HSP70 and deficiency of neoantigen presentation. To address this problem, we designed a photothermal-responsive on-demand controlled drug release gold nanosystem to carry BRAF inhibitor. The nano-system can be specifically delivered into tumor cells rather than Tcells, and effectively transformed the optical energy into heat energy upon laser irradiation. Combination of photothermal and targeted therapy significantly promoted immunogenic cell death and T-cell infiltration. On top of this regimen, systematically administration of PD-1 antibody not only suppressed local-treated tumor but also inhibited abscopal tumor by enhancing generalized immune-related antitumor response. More importantly, the triple-combo regimen could efficiently convert immune ?cold? tumors into ?hot? ones. In conclusion, our research proves the advantage of photothermal-targeted-immune triple combinatorial regimen in treating tumors which are clinical unresectable multifocal and lack of T-cell infiltration.