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Gewählte Publikation:

Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Letter

Jahr: 2015

AutorInnen: 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

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

Quelle: Nature. 2015; 521(7550):94-98



Autor/innen der Vetmeduni Vienna:

Kenner Lukas

Beteiligte Vetmed-Organisationseinheiten
Institut für Pathologie, Abteilung für Labortierpathologie


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.

Keywords Pubmed: Adoptive Transfer
Animals
Antibodies, Neoplasm/immunology
Antineoplastic Agents/immunology
Antineoplastic Agents/pharmacology
B7-H1 Antigen/metabolism
Cells, Cultured
Chemokine CXCL13/metabolism
Humans
I-kappa B Kinase/metabolism
Immunoglobulin A/immunology
Interleukin-10/immunology
Lymphocyte Activation/drug effects
Male
Mice
Mice, Inbred C57BL
Neoplastic Stem Cells/pathology
Organoplatinum Compounds/administration & dosage
Organoplatinum Compounds/immunology
Organoplatinum Compounds/pharmacology*
Organoplatinum Compounds/therapeutic use
Oxaliplatin
Plasma Cells/cytology
Plasma Cells/drug effects*
Plasma Cells/immunology*
Prostatic Neoplasms/drug therapy*
Prostatic Neoplasms/immunology*
Prostatic Neoplasms/pathology
Receptors, Transforming Growth Factor beta/metabolism
Signal Transduction
T-Lymphocytes, Cytotoxic/cytology
T-Lymphocytes, Cytotoxic/drug effects*
T-Lymphocytes, Cytotoxic/immunology*
Transforming Growth Factor beta/immunology


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