Stimulatory and Suppressive NK Cell, DC, and MDSC Interactions in Human Cancer

描述（由申请人提供）：自然杀伤（NK）细胞最近被认为是适应性免疫的关键调节剂。特别是，NK细胞与树突状细胞（DC）的相互作用是形成有效抗癌免疫反应的核心，对DC和其他基于细胞的癌症免疫治疗具有重要意义。我们之前已经证明，与il -2激活的“杀伤”NK细胞能够消除免疫刺激的DC相比，il -18激活的“辅助”NK细胞可以通过DC激活和增强DC诱导的1型免疫来增强抗肿瘤免疫反应。然而，我们新的初步数据表明，这种IL-18激活的NK细胞也可能通过髓源性抑制细胞（MDSCs）的过度激活而具有不良的免疫抑制功能，并通过MDSCs中的自分泌cox - pge2反馈加强。这进一步表明，COX2-PGE2轴抑制可能逆转nk介导的MDSC功能上调，同时保持或增强nk介导的DC激活。在本提案中，使用IL-2和il -18激活的NK细胞作为模型，我试图确定“杀手”和“辅助”NK细胞不同地获得和执行所需的免疫刺激（肿瘤杀伤、MDSC杀伤和dc激活）和不需要的免疫抑制（dc杀伤和MDSC激活）功能的机制。这种机制知识随后将用于检查潜在的药理学或生物学方法来修饰NK细胞与dc和MDSCs的相互作用，以最大限度地提高理想的抗癌免疫反应。总体而言，该项目将为NK细胞与dc和MDSCs的免疫刺激和免疫抑制相互作用的获取和性能提供新的功能和机制见解，并将确定这些理想和不理想的NK细胞活性的治疗分离靶点，以改善癌症免疫治疗。

DESCRIPTION (provided by applicant): Natural killer (NK) cells have been recently implicated as critical modulators of adaptive immunity. In particular, NK cell interactions with dendritic cels (DCs) are central to shaping effective anti-cancer immune responses, holding great implications for DC- and other cell-based cancer immunotherapies. We have previously demonstrated that, in contrast to IL-2-activated 'killer' NK cells capable of eliminating immune-stimulatory DCs, IL-18-activated 'helper' NK cells can potentiate anti-tumor immune responses through DC activation and the enhancement of DC-induced type-1 immunity. However, our new preliminary data indicate that such IL-18- activated NK cells may also have undesirable immune-suppressive functions through the hyper-activation of myeloid-derived suppressor cells (MDSCs), reinforced by autocrine COX2-PGE2 feedback in MDSCs. This further suggests the possibility of COX2-PGE2 axis inhibition in reversing the NK-mediated up-regulation of MDSC functions, while preserving or enhancing NK-mediated DC activation. In this proposal, using IL-2- and IL-18-activated NK cells as a model, I seek to identify the mechanisms by which 'killer' and 'helper' NK cells differentially acquire and perform desirable immune-stimulatory (tumor- killing, MDSC-killing, and DC-activating) and undesirable immune-suppressive (DC-killing and MDSC- activating) functions. This mechanistic knowledge will be subsequently used to examine potential pharmacologic or biologic methods of modifying NK cell interactions with DCs and MDSCs to maximize desirable anti-cancer immune responses. Overall, this project will provide new functional and mechanistic insights into the acquisition and performance of NK cell immune-stimulatory and immune-suppressive interactions with DCs and MDSCs, and will identify targets for the therapeutic separation of these desirable and undesirable NK cell activities for the improvement of cancer immunotherapy.