Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy.
Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy.
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DOI：
10.1038/nature14395
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发表时间：
2015-05-07
期刊：
影响因子：
64.8
通讯作者：
Karin M
中科院分区：
文献类型：
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作者：
Shalapour S;Font-Burgada J;Di Caro G;Zhong Z;Sanchez-Lopez E;Dhar D;Willimsky G;Ammirante M;Strasner A;Hansel DE;Jamieson C;Kane CJ;Klatte T;Birner P;Kenner L;Karin M
癌症相关的遗传改变诱导肿瘤抗原的表达，这些抗原可以激活CD 8+细胞毒性T细胞（CTL），但已建立的肿瘤的微环境通过知之甚少的机制促进免疫耐受。最近开发的克服致耐受性机制的治疗剂激活肿瘤导向的CTL，并且在一些人类癌症中有效。免疫机制也影响治疗结果，某些化疗药物通过诱导免疫原性细胞死亡（ICD）和其他效应机制刺激癌症特异性免疫应答。我们以前的研究表明，B淋巴细胞被CXCL 13募集到前列腺癌（PC）中，通过产生激活PC干细胞中IKKα-Bmi 1模块的光毒素（LT）来促进去势抵抗性PC（CRPC）。由于CRPC对大多数治疗是难治性的，我们研究了B细胞参与获得化疗耐药性。我们将这项研究集中在奥沙利铂上，奥沙利铂是一种免疫原性化疗药物，对侵袭性PC有效。我们发现，B细胞调节对低剂量奥沙利铂的反应，奥沙利铂通过诱导ICD促进肿瘤定向CTL活化。三种不同的小鼠PC模型对奥沙利铂难治，除非B细胞在遗传上或免疫学上耗竭。关键的免疫抑制性B细胞是表达伊加、IL-10和PD-L1的浆细胞，其外观取决于TGFβ受体（TGFβR）信号传导。这些细胞也浸润人类耐药PC，消除这些细胞可以实现奥沙利铂治疗肿瘤的CTL依赖性根除。
Cancer-associated genetic alterations induce expression of tumor antigens which can activate CD8+ cytotoxic T cells (CTL), but the microenvironment of established tumors promotes immune tolerance through poorly understood mechanisms. Recently developed therapeutics that overcome tolerogenic mechanisms activate tumor-directed CTL 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 (ICD) and other effector mechanisms. Our previous studies revealed that B lymphocytes recruited by CXCL13 into prostate cancer (PC) promote castrate-resistant PC (CRPC) by producing lymphotoxin (LT) which activates an IKKα-Bmi1 module in PC stem cells. Since CRPC is refractory to most therapies, we examined B cell involvement in acquisition of chemotherapy resistance. We focused this study on oxaliplatin, an immunogenic chemotherapeutic that is effective in aggressive PC. We found that B cells modulate the response to low dose oxaliplatin, which by inducing ICD promotes tumor-directed CTL activation. Three different mouse PC models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The critical immunosuppressive B cells are plasmocytes that express IgA, IL-10 and PD-L1, whose appearance depends on TGFβ-receptor (TGFβR) signaling. Elimination of these cells, which also infiltrate human therapy-resistant PC, allows CTL-dependent eradication of oxaliplatin-treated tumors.