Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy

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

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180 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)94-98
Number of pages5
JournalNature
Volume521
Issue number7550
DOIs
StatePublished - May 7 2015
Externally publishedYes

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Shalapour, S., Font-Burgada, J., Di Caro, G., Zhong, Z., Sanchez-Lopez, E., Dhar, D., Willimsky, G., Ammirante, M., Strasner, A., Hansel, D. E., Jamieson, C., Kane, C. J., Klatte, T., Birner, P., Kenner, L., & Karin, M. (2015). Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature, 521(7550), 94-98. https://doi.org/10.1038/nature14395