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Nature:肿瘤对“奥沙利铂”的抵抗力

标签:奥沙利铂 癌症
摘要 : “奥沙利铂”(一种能够产生免疫性的化疗药物)对治疗侵袭性前列腺癌是有效的,但与大多数其他已知的治疗药物相同的是,去势抗性前列腺癌会对持续治疗产生抵抗力。

“奥沙利铂”(一种能够产生免疫性的化疗药物)对治疗侵袭性前列腺癌是有效的,但与大多数其他已知的治疗药物相同的是,去势抗性前列腺癌会对持续治疗产生抵抗力。这项研究显示,IgA浆细胞在前列腺癌小鼠模型中能够通过抑制因免疫作用而发生的肿瘤细胞死亡和通过对细胞毒性淋巴细胞的激发来促进对“奥沙利铂”的抵抗力。免疫抑制性浆细胞会响应于TGFβ而生成,它们的功能取决于“程序化死亡配体-1”和“白介素-10”的表达。这些IgA浆细胞(它们也会渗透进对治疗有抵抗力的人类前列腺癌)的清除,使得用“奥沙利铂”治疗过的肿瘤能够通过以依赖于细胞毒性T-细胞的方式被根除。

原文链接:

Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy

原文摘要:

Cancer-associated genetic alterations induce expression of tumour antigens that can activate CD8+cytotoxic T cells (CTLs), but the microenvironment of established tumours promotes immune tolerance through poorly understood mechanisms1. Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers. Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms. Our previous studies revealed that B cells recruited by the chemokine CXCL13 into prostate cancer tumours promote the progression of castrate-resistant prostate cancer by producing lymphotoxin, which activates an IκB kinase α (IKKα)-BMI1 module in prostate cancer stem cells. Because castrate-resistant prostate cancer is refractory to most therapies, we examined B cell involvement in the acquisition of chemotherapy resistance. Here we focus on oxaliplatin, an immunogenic chemotherapeutic agent, that is effective in aggressive prostate cancer. We show that mouse B cells modulate the response to low-dose oxaliplatin, which promotes tumour-directed CTL activation by inducing immunogenic cell death. Three different mouse prostate cancer models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGFβ receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.

来源: Nature 浏览次数:0

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