Publication Date:
2015-04-30
Description:
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 IkappaB kinase alpha (IKKalpha)-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 TGFbeta receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501632/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501632/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- AI043477/AI/NIAID NIH HHS/ -- CA127923/CA/NCI NIH HHS/ -- R01 AI043477/AI/NIAID NIH HHS/ -- R01 CA127923/CA/NCI NIH HHS/ -- England -- Nature. 2015 May 7;521(7550):94-8. doi: 10.1038/nature14395. Epub 2015 Apr 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Institute of Immunology, Charite Campus Buch, 13125 Berlin, Germany. ; Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, San Diego, California 92093, USA. ; Department of Surgery, Urology Division, University of California San Diego, 3855 Health Sciences Drive, San Diego, California 92093, USA. ; Department of Urology, Medical University of Vienna, 1090 Vienna, Austria. ; Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25924065" target="_blank"〉PubMed〈/a〉
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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