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器。特别是，NK细胞与树突状细胞(DC)的相互作用是形成有效的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。我们先前已经证明，与IL-2激活的NK细胞清除免疫刺激性DC的能力不同，IL-18激活的辅助NK细胞可以通过DC激活和DC诱导的1型免疫增强来增强抗肿瘤免疫反应。然而，我们的新的初步数据表明，这种IL-18激活的NK细胞也可能通过髓系来源的抑制细胞(MDSCs)的过度激活而具有不良的免疫抑制功能，MDSCs的自分泌COX2-PGE2反馈加强了MDSCs的免疫抑制功能。这进一步表明，COX2-PGE2轴抑制在逆转NK介导的MDSC功能上调的同时，保留或增强NK介导的DC激活的可能性。在这个方案中，我试图以IL-2和IL-18激活的NK细胞为模型，确定NK细胞获得和执行理想的免疫刺激(肿瘤杀伤、MDSC杀伤和DC激活)和不理想的免疫抑制(DC杀伤和MDSC激活)功能的机制。这一机制知识随后将被用于研究潜在的药理学或生物学方法，以改变NK细胞与DC和MDSCs的相互作用，以最大限度地发挥所需的抗癌免疫反应。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得和表现提供新的功能和机制方面的见解，并将确定用于治疗分离这些可取和不可取的NK细胞活动的靶点，以改进癌症免疫治疗。

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.