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Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy

机译：免疫抑制浆细胞阻碍T细胞依赖性免疫原性化疗

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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 mechanisms(1,2). Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers(1). Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms(3,4). 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 IkB kinase a (IKK alpha)-BMI1 module in prostate cancer stem cells(5,6). 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(3,4) that is effective in aggressive prostate cancer(7). 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 TGF beta receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.
机译：癌症相关的遗传改变诱导表达可以激活CD8（+）细胞毒性T细胞（CTL）的肿瘤抗原，但已建立的肿瘤的微环境通过人们了解的机制促进了免疫耐受（1,2）。克服耐受性机制的最新开发的疗法可激活肿瘤定向的CTL，并在某些人类癌症中有效（1）。免疫机制也影响治疗结果，某些化学治疗药物通过诱导免疫原性细胞死亡和其他效应器机制刺激癌症特异性免疫反应（3,4）。我们以前的研究表明，趋化因子CXCL13募集的B细胞通过产生淋巴毒素来促进去势抵抗性前列腺癌的发展，该毒素激活了前列腺癌干细胞中的IkB激酶a（IKK alpha）-BMI1模块（5， 6）。由于去势抵抗性前列腺癌对大多数疗法均无效，因此我们检查了B细胞在获得化疗耐药性中的作用。在这里，我们重点研究奥沙利铂，一种可有效治疗侵袭性前列腺癌的免疫原性化疗药物（3,4）。我们显示，小鼠B细胞调节对低剂量奥沙利铂的反应，其通过诱导免疫原性细胞死亡促进肿瘤定向CTL活化。除非在遗传或药理上减少了B细胞，否则三种不同的小鼠前列腺癌模型对奥沙利铂难治。至关重要的免疫抑制B细胞是表达IgA，白介素（IL）-10和程序性死亡配体1（PD-L1）的浆细胞，其出现取决于TGFβ受体的信号传导。消除这些细胞，这些细胞也会浸润对人类治疗有抵抗力的前列腺癌，从而可以根除草酸铂，从而根除奥沙利铂治疗的肿瘤。

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  • 来源
    《Nature》 |2015年第7550期|94-98|共5页
  • 作者

    Shalapour Shabnam; Font-Burgada Joan; Di Caro Giuseppe; Zhong Zhenyu; Sanchez-Lopez Elsa; Dhar Debanjan; Willimsky Gerald; Ammirante Massimo; Strasner Amy; Hansel Donna E.; Jamieson Christina; Kane Christopher J.; Klatte Tobias; Birner Peter; Kenner Lukas; Karin Michael;

  • 作者单位

    UCSD, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA|Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA;

    UCSD, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA|Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA;

    UCSD, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA|Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA;

    UCSD, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA|Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA;

    UCSD, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA|Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA;

    UCSD, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA|Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA;

    Charite Campus Buch, Inst Immunol, D-13125 Berlin, Germany;

    UCSD, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA|Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA;

    UCSD, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA|Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Div Urol, Dept Surg, San Diego, CA 92093 USA;

    Univ Calif San Diego, Div Urol, Dept Surg, San Diego, CA 92093 USA;

    Med Univ Vienna, Dept Urol, A-1090 Vienna, Austria;

    Med Univ Vienna, Dept Pathol, A-1090 Vienna, Austria;

    Med Univ Vienna, Dept Pathol, A-1090 Vienna, Austria|Univ Vet Med Vienna, Med Univ Vienna, Ludwig Boltzmann Inst Canc Res, Clin Inst Pathol,UPLA, A-1210 Vienna, Austria;

    UCSD, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA|Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA;

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