Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy.
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.
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.
Shabnam
S
Shalapour
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.
Joan
J
Font-Burgada
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.
Giuseppe
G
Di Caro
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.
Zhenyu
Z
Zhong
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.
Elsa
E
Sanchez-Lopez
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.
Debanjan
D
Dhar
Institute of Immunology, Charité Campus Buch, 13125 Berlin, Germany.
Gerald
G
Willimsky
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.
Massimo
M
Ammirante
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.
Amy
A
Strasner
Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, San Diego, California 92093, USA.
Donna E
DE
Hansel
Department of Surgery, Urology Division, University of California San Diego, 3855 Health Sciences Drive, San Diego, California 92093, USA.
Christina
C
Jamieson
Department of Surgery, Urology Division, University of California San Diego, 3855 Health Sciences Drive, San Diego, California 92093, USA.
Christopher J
CJ
Kane
Department of Urology, Medical University of Vienna, 1090 Vienna, Austria.
Tobias
T
Klatte
Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
Peter
P
Birner
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.
Lukas
L
Kenner
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.
Michael
M
Karin
D019264:Adoptive Transfer; D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000378:metabolism; D002478:Cells, Cultured; D054382:Chemokine CXCL13 / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007070:Immunoglobulin A / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D000077150:Oxaliplatin; D010950:Plasma Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C110663:CXCL13 protein, human; C498919:Cd274 protein, mouse; D054382:Chemokine CXCL13; D007070:Immunoglobulin A; D009944:Organoplatinum Compounds; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000077150:Oxaliplatin; D016753:Interleukin-10; D051550:I-kappa B Kinase