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

  • Author(s): 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
  • et al.
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.

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