Journal Article

Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy

Karin, Michael, Willimsky, Gerald, Font-Burgada, Joan, Hansel, Donna E., Jamieson, Christina, Dhar, Debanjan, Ammirante, Massimo, Zhong, Zhenyu, Sanchez-Lopez, Elsa, Klatte, Tobias, Di Caro, Giuseppe, Birner, Peter, Kenner, Lukas, Kane, Christopher J., Shalapour, Shabnam, Strasner, Amy

2015

Overview

IgA plasmocytes are shown to promote resistance to the immunogenic chemotherapeutic oxaliplatin in prostate cancer mouse models by inhibiting activation of cytotoxic T cells; immunosuppressive plasma cells, which are also found in human-therapy-resistant prostate cancer, are generated in response to TGFβ, and their functionality depends on PD-L1 expression and IL-10 secretion. Tumour resistance to oxaliplatin Oxaliplatin, an immunogenic chemotherapeutic, is effective in aggressive prostate cancer, but as with most other known therapeutics, castration-resistant forms of the cancer become refractory to continued treatment. This study shows that IgA plasmocytes promote resistance to oxaliplatin in prostate cancer mouse models by inhibiting immunogenic tumour cell death and through activation of cytotoxic lymphocytes. Immunosuppressive plasma cells are generated in response to TGFβ, and their functionality depends on the expression of programmed death ligand 1 and interleukin 10. Elimination of these IgA plasmocytes, which also infiltrate human-therapy-resistant prostate cancer, allows cytotoxic-T-cell-dependent eradication of oxaliplatin-treated tumours. 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 1 , 2 . Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers 1 . Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms 3 , 4 . 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 5 , 6 . 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 3 , 4 that is effective in aggressive prostate cancer 7 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67 / 631/67/580 / Adoptive Transfer / Animals / Antibodies, Neoplasm - immunology / Antineoplastic Agents - immunology / Antineoplastic Agents - pharmacology / B7-H1 Antigen - metabolism / Cancer / Cancer therapies / Cells, Cultured / Chemokine CXCL13 - metabolism / Chemotherapy / DNA damage / Health aspects / Humanities and Social Sciences / Humans / I-kappa B Kinase - metabolism / Identification and classification / Immune response / Immune system / Immunoglobulin A - immunology / Immunoglobulins / Interleukin-10 - immunology / letter / Lymphocyte Activation - drug effects / Lymphocytes / Male / Metastasis / Methods / Mice / Mice, Inbred C57BL / Mortality / multidisciplinary / Neoplastic Stem Cells - pathology / Organoplatinum Compounds - administration & dosage / Organoplatinum Compounds - immunology / Organoplatinum Compounds - pharmacology / Organoplatinum Compounds - therapeutic use / Oxaliplatin / Phosphorylation / Plasma cells / Plasma Cells - cytology / Plasma Cells - drug effects / Plasma Cells - immunology / Prostate cancer / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - immunology / Prostatic Neoplasms - pathology / Receptors, Transforming Growth Factor beta - metabolism / Science / Signal Transduction / Skin cancer / Stem cells / T cells / T-Lymphocytes, Cytotoxic - cytology / T-Lymphocytes, Cytotoxic - drug effects / T-Lymphocytes, Cytotoxic - immunology / Transforming Growth Factor beta - immunology / Tumors