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Cancer Res.:化疗介导自噬增强肿瘤细胞免疫治疗的敏感性

8月31日,Cancer Research 杂志电,自噬抑制常规化疗的疗效,但其对免疫的影响研究甚少。本研究发现,化疗使肿瘤细胞更容易被体内的细胞毒性T细胞(CTL)所溶解。此外,不表达抗原的旁观者肿瘤细胞同样被CTL杀死。这种效果,是肿瘤细胞表面的甘露糖-6 - 磷酸受体(MPR)短暂却显著的表达上调所介导的。

综合治疗方法的抗肿瘤效果与MPR上调密切相关。阻断这种上调将削弱免疫治疗和化疗的综合治疗效应。在进行化疗的,多种小鼠肿瘤模型和多发性骨髓瘤患者中,研究者均观察到MPR在肿瘤细胞表面的积累。值得一提的是,化疗诱导的自噬作用是导致这种受体再分配的原因。

总之,本研究结果揭示了一个传统的癌症化疗和免疫治疗的抗肿瘤作用的分子机制。(生物谷bioon.com)


参考文献:


Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy

DOI:doi:
AUTHORS:Rupal Ramakrishnan1, Chun huang2, Hyun-Il Cho1, Mark Lloyd3, Joseph Johnson4, Xiubao Ren5, Soner Altiok6, Daniel Sullivan7, Jeffrey Weber8, Esteban Celis9, and Dmitry I. Gabrilovich1,*
ABSTRACT:Autophagy attenuates the efficacy of conventional chemotherapy but its effects on immunotherapy have been little studied. Here we report that chemotherapy renders tumor cells more susceptible to lysis by cytotoxic T cells (CTL) in vivo. Moreover, bystander tumor cells that did not express antigen were killed by CTL. This effect was mediated by transient but dramatic upregulation of the mannose-6-phosphate receptor (MPR) on the tumor cell surface. Antitumor effects of combined treatment related to the kinetics of MPR upregulation and abrogation of this event abolished the combined effect of immunotherapy and chemotherapy. MPR accumulation on the tumor cell surface during chemotherapy was observed in different mouse tumor models and in patients with multiple myeloma. Notably, this effect was the result of redistribution of the receptor caused by chemotherapy-inducible autophagy. Together, our findings reveal one molecular mechanism through which the antitumor effects of conventional cancer chemotherapy and immunotherapy are realized.

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