Journal
NATURE
Volume 521, Issue 7550, Pages 94-U235Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature14395
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Funding
- National Institutes of Health (NIH) [CA127923, AI043477]
- DFG
- German Cancer Consortium [TR36, DKTK]
- Genome Research-Austria project 'Inflammobiota' (FWF) [P26011]
- Cure Search Foundation
- German Research Foundation (DFG) [SH721/1-1]
- Irvington-CRI
- CIRM [TG2-01154]
- FIRC/AIRC
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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.
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