Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy

Cancer-associated genetic alterations induce expression of tumor antigens which can activate CD8(+) cytotoxic T cells (CTL), but the microenvironment of established tumors promotes immune tolerance through poorly understood mechanisms(1,2). Recently developed therapeutics that overcome tolerogenic mechanisms activate tumor-directed CTL 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 (ICD) and other effector mechanisms(3,4). Our previous studies revealed that B lymphocytes recruited by CXCL13 into prostate cancer (PC) promote castrate-resistant PC (CRPC) by producing lymphotoxin (LT) which activates an IKKα-Bmi1 module in PC stem cells(5,6). Since CRPC is refractory to most therapies, we examined B cell involvement in acquisition of chemotherapy resistance. We focused this study on oxaliplatin, an immunogenic chemotherapeutic(3,4) that is effective in aggressive PC(7). We found that B cells modulate the response to low dose oxaliplatin, which by inducing ICD promotes tumor-directed CTL activation. Three different mouse PC models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The critical immunosuppressive B cells are plasmocytes that express IgA, IL-10 and PD-L1, whose appearance depends on TGFβ-receptor (TGFβR) signaling. Elimination of these cells, which also infiltrate human therapy-resistant PC, allows CTL-dependent eradication of oxaliplatin-treated tumors

Inflammasomes: mechanism of action, role in disease, and therapeutics

The inflammasomes are innate immune system receptors/sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived from host proteins. It has been implicated in a host of inflammatory disorders. Recent developments have greatly enhanced our understanding of the molecular mechanisms by which different inflammasomes are activated. Additionally, increasing evidence in mouse models, supported by human data, strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health such as metabolic disorders and neurodegenerative diseases. Finally, recent developments pointing toward promising therapeutics that target inflammasome activity in inflammatory diseases have been reported. This review will focus on these three areas of inflammasome research