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

Research output: Contribution to journalArticle

174 Citations (Scopus)

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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oxaliplatin
Immunosuppressive Agents
Plasma Cells
Prostatic Neoplasms
T-Lymphocytes
Drug Therapy
B-Lymphocytes
Neoplasms
Chemokine CXCL13
Cell Death
Cellular Microenvironment
Lymphotoxin-alpha
Immune Tolerance
Neoplastic Stem Cells
Neoplasm Antigens
Interleukin-10
Immunoglobulin A
Phosphotransferases
Therapeutics
Ligands

ASJC Scopus subject areas

  • General

Cite this

Shalapour, S., Font-Burgada, J., Di Caro, G., Zhong, Z., Sanchez-Lopez, E., Dhar, D., ... Karin, M. (2015). Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature, 521(7550), 94-98. https://doi.org/10.1038/nature14395

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

In: Nature, Vol. 521, No. 7550, 07.05.2015, p. 94-98.

Research output: Contribution to journalArticle

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 2015, 'Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy', Nature, vol. 521, no. 7550, pp. 94-98. https://doi.org/10.1038/nature14395
Shalapour S, Font-Burgada J, Di Caro G, Zhong Z, Sanchez-Lopez E, Dhar D et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature. 2015 May 7;521(7550):94-98. https://doi.org/10.1038/nature14395
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. / Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. In: Nature. 2015 ; Vol. 521, No. 7550. pp. 94-98.
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