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Nature. 2015 May 7;521(7550):94-8. doi: 10.1038/nature14395. Epub 2015 Apr 29.

Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy.

Author information

1
1] Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, San Diego, California 92093, USA [2] Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, San Diego, California 92093, USA.
2
Institute of Immunology, Charité Campus Buch, 13125 Berlin, Germany.
3
Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, San Diego, California 92093, USA.
4
Department of Surgery, Urology Division, University of California San Diego, 3855 Health Sciences Drive, San Diego, California 92093, USA.
5
Department of Urology, Medical University of Vienna, 1090 Vienna, Austria.
6
Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
7
1] Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria [2] Clinical Institute of Pathology, Ludwig Boltzmann Institute for Cancer Research, Medical University of Vienna, Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine Vienna, 1210 Vienna, Austria.

Abstract

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. 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.

PMID:
25924065
PMCID:
PMC4501632
DOI:
10.1038/nature14395
[Indexed for MEDLINE]
Free PMC Article

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