Maquetación 1

Summary. Renal cell carcinoma is increasing in frequency in the United States and is often detected late in the course of disease due to nonspecific symptoms. A subset of renal cell carcinoma is attributable to familial or hereditary syndromes, including von Hippel-Lindau and Birt-Hogg-Dubé syndromes, among others. Understanding of the molecular alterations in patients with familial syndromes may provide some insight into the underlying mechanisms of disease initiation and progression. This review describes the various subtypes of renal cell carcinoma and the familial syndromes associated with these tumors

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