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的抗癌免疫应答的核心，对DC和其他基于细胞的癌症免疫疗法具有重大意义。我们先前已经证明，与能够消除免疫刺激性DC的IL-2激活的“杀伤”NK细胞相反，IL-18激活的“辅助”NK细胞可以通过DC激活和DC诱导的1型免疫的增强来增强抗肿瘤免疫应答。然而，我们的新的初步数据表明，这种IL-18激活的NK细胞也可能通过骨髓源性抑制细胞（MDSC）的过度激活而具有不期望的免疫抑制功能，并通过MDSC中的自分泌COX 2-PGE 2反馈来加强。这进一步表明了COX 2-PGE 2轴抑制逆转NK介导的MDSC功能上调的可能性，同时保留或增强NK介导的DC活化。在这个提议中，使用IL-2和IL-18激活的NK细胞作为模型，我试图确定“杀伤”和“辅助”NK细胞差异地获得和执行期望的免疫刺激（肿瘤杀伤、MDSC杀伤和DC激活）和不期望的免疫抑制（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修饰NK细胞与DC和MDSC相互作用的潜在药理学或生物学方法，以最大化期望的抗癌免疫应答。总的来说，该项目将为NK细胞与DC和MDSC的免疫刺激和免疫抑制相互作用的获得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细胞活性的治疗性分离的靶点，以改善癌症免疫治疗。 公共卫生相关性：癌症仍然是美国85岁以下死亡的主要原因，这突出表明需要创新的癌症治疗方法，包括提高免疫反应对癌症的有效性的策略。使用高度相关的人类肿瘤模型和临床癌症材料，该提案旨在定义对癌症的免疫应答和免疫逃避至关重要的三种细胞类型之间的关键相互作用：自然杀伤（NK）细胞，树突状细胞和骨髓来源的抑制细胞。这项研究的结果将直接有助于改善基于细胞的癌症治疗， 为选择性增强免疫刺激性抗癌NK细胞活性的策略提供信息。

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. PUBLIC HEALTH RELEVANCE: Cancer remains the leading cause of death under age 85 in the US, highlighting the need for innovative approaches to cancer treatment, including strategies to enhance the effectiveness of immune responses against cancer. Using highly-relevant human tumor models and clinical cancer materials, this proposal seeks to define the key interactions between three cell types critical to the immune response and immune evasion of cancer: natural killer (NK) cells, dendritic cells, and myeloid-derived suppressor cells. The results of this study will directly contribute to the improvement of cell-based cancer therapies by informing strategies for the selective enhancement of immune-stimulatory anti-cancer NK cell activities.