【原创】Cancer Res.：敲除NLRP3蛋白可使肿瘤对治疗性癌症疫苗的反应增强四倍

疫苗的制造非常的困难。由于疫苗具有个体特异性，需要通过个体免疫细胞产生，因而疫苗的生产过程要求必须首先从患者体内分离出免疫细胞，然后将其运送至公司再生成特异的疫苗。这使得疫苗的价格非常的昂贵。Provenge用于三次治疗的花费大约是在10万美元。

“癌症疫苗无法像药片一样进行批量生产，”Serody解释说：“此外，它也不同于对抗病毒的疫苗例如脊髓灰质炎疫苗和天花疫苗。癌细胞有时候会‘欺骗’我们的身体，将它视为我们身体内的正常细胞，从而逃避机体的免疫系统。我们希望我们的研究将推动开发出更有效的疫苗对抗多种癌症类型。”（
Cancer Res. doi: 10.1158/0008-5472.CAN-10-1921

The Inflammasome Component Nlrp3 Impairs Antitumor Vaccine by Enhancing the Accumulation of Tumor-Associated Myeloid-Derived Suppressor Cells

Hendrik W. van Deventer1, Joseph E. Burgents2, Qing Ping Wu3, Rita-Marie T. Woodford4, W. June Brickey2,3, Irving C. Allen2, Erin McElvania-Tekippe2, Jonathan S. Serody1,2,3, and Jenny P.-Y. Ting2,3,4

Abstract

The inflammasome is a proteolysis complex that generates the active forms of the proinflammatory cytokines interleukin (IL)-1β and IL-18. Inflammasome activation is mediated by NLR proteins that respond to microbial and nonmicrobial stimuli. Among NLRs, NLRP3 senses the widest array of stimuli and enhances adaptive immunity. However, its role in antitumor immunity is unknown. Therefore, we evaluated the function of the NLRP3 inflammasome in the immune response using dendritic cell vaccination against the poorly immunogenic melanoma cell line B16-F10. Vaccination of Nlrp3?/? mice led to a relative 4-fold improvement in survival relative to control animals. Immunity depended on CD8+ T cells and exhibited immune specificity and memory. Increased vaccine efficacy in Nlrp3?/? hosts did not reflect differences in dendritic cells but rather differences in myeloid-derived suppressor cells (MDSC). Although Nlrp3 was expressed in MDSCs, the absence of Nlrp3 did not alter either their functional capacity to inhibit T cells or their presence in peripheral lymphoid tissues. Instead, the absence of Nlrp3 caused a 5-fold reduction in the number of tumor-associated MDSCs found in host mice. Adoptive transfer experiments also showed that Nlrp3?/? MDSCs were less efficient in reaching the tumor site. Depleting MDSCs with an anti–Gr-1 antibody increased the survival of tumor-bearing wild-type mice but not Nlrp3?/? mice. We concluded that Nlrp3 was critical for accumulation of MDSCs in tumors and for inhibition of antitumor T-cell immunity after dendritic cell vaccination. Our findings establish an unexpected role for Nlrp3 in impeding antitumor immune responses, suggesting novel approaches to improve the response to antitumor vaccines by limiting Nlrp3 signaling.