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

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.

• Authors: Shabnam Shalapour, Joan Font-Burgada, Giuseppe Di Caro, Zhenyu Zhong, Elsa Sanchez-Lopez, Debanjan Dhar, Gerald Willimsky, Massimo Ammirante, Amy Strasner, Donna E Hansel, Christina Jamieson, Christopher J Kane, Tobias Klatte, Peter Birner, Lukas Kenner, Michael Karin
• Journal: Nature (Nature) Vol. 521 Issue 7550 Pg. 94-8 (May 07 2015) ISSN: 1476-4687 [Electronic] England
• PMID: 25924065 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neoplasm
• Antineoplastic Agents
• B7-H1 Antigen
• CXCL13 protein, human
• Cd274 protein, mouse
• Chemokine CXCL13
• Immunoglobulin A
• Organoplatinum Compounds
• Receptors, Transforming Growth Factor beta
• Transforming Growth Factor beta
• Oxaliplatin
• Interleukin-10
• I-kappa B Kinase

Topics

• Adoptive Transfer
• Animals
• Antibodies, Neoplasm (immunology)
• Antineoplastic Agents (immunology, 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, immunology, pharmacology, therapeutic use)
• Oxaliplatin
• Plasma Cells (cytology, drug effects, immunology)
• Prostatic Neoplasms (drug therapy, immunology, pathology)
• Receptors, Transforming Growth Factor beta (metabolism)
• Signal Transduction
• T-Lymphocytes, Cytotoxic (cytology, drug effects, immunology)
• Transforming Growth Factor beta (immunology)