Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy

Article

关键词: GENE-EXPRESSION ANALYSIS;    INFILTRATING B-CELLS;    PROSTATE-CANCER;    TARGETED DELETION;    MICE;    AUTOIMMUNITY;    METASTASIS;    MECHANISMS;    IMMUNITY;    THERAPY;   

DOI  :  10.1038/nature14395

来源: SCIE

【 摘 要 】

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 IkB kinase a (IKK alpha)-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 TGF beta receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.

【 授权许可】

Free