CONTROLLING NK CELL ANTI-CANCER ACTIVITY: THE ROLE OF NUTRIENTS AND SUPPLEMENTS

描述（由申请人提供）：自然杀伤细胞通常被视为癌症免疫监视的第一道防线，是免疫介导的癌症排斥反应的关键参与者。我们最近描述了一种新的非常规NK细胞亚群，它们存在于粘膜组织中，其特征在于产生大量IL-22。我们将这种新的细胞亚群称为NK-22。虽然这些细胞的起源仍不清楚，它们与传统NK细胞的关系也存在争议，但我们和其他人已经表明，当暴露于炎性细胞因子时，这些细胞可以获得传统NK细胞的典型特征。此外，最近的研究表明，类似的细胞类型在启动肿瘤排斥反应中起着关键作用。 我们的初步数据表明，NK-22高度依赖于转录因子芳烃受体（AHR）的发展。已知AHR结合与抗肿瘤活性相关的膳食化合物，如吲哚-3-甲醇（I3 C）和类黄酮。我们假设，通过膳食补充剂参与AHR，我们可以操纵NK-22的数量和/或活性。在具体目标1中，我们将测试I3 C和类黄酮槲皮素对NK-22扩增和体内功能的影响。在具体目标2中，我们将确定这些补充剂是否影响NK-22在自发和可移植肿瘤模型中的抗肿瘤功能。 我们发现了NK-22，有助于其发展和功能的初步表征，并产生了独特的NK-22特异性试剂以及在几种免疫和非免疫细胞类型中缺乏NK-22或AHR的小鼠品系。因此，我们处于一个独特的位置，可以直接测试据称与抗癌活性相关的特定膳食补充剂对先天免疫细胞肿瘤监测的影响。!

DESCRIPTION (provided by applicant): Natural killer cells are generally viewed as a first line of defense in cancer immunosurveillance and are critical players in immune-mediated cancer rejection. We have recently described a new subset of unconventional NK cells that reside in mucosal tissues and are characterized by production of large amounts of IL-22. We refer to this novel cell subset as NK-22. Although the origin of these cells is still unclear and their relationship to conventional NK cells a matter of debate, we and others have shown that these cells can acquire features typical of conventional NK cells when exposed to inflammatory cytokines. Moreover, recent work has suggested that a similar cell type plays a critical role in initiating tumor rejection. Our preliminary data show that NK-22 are highly dependent on the transcription factor aryl hydrocarbon receptor (AHR) for their development. AHR is known to bind dietary compounds such as indol-3-carbinol (I3C) and flavonoids that are associated with anti-tumor activity. We hypothesize that by engaging AHR through dietary supplements, we can manipulate the numbers and or the activity of NK-22. In Specific Aim 1 we will test the effect of I3C and the flavonoid quercetin on NK-22 expansion and function in vivo. In Specific Aim 2 we will determine whether these supplements impact the anti-tumor function of NK-22 in spontaneous and transplantable tumor models. We discovered NK-22, contributed to the initial characterization of their development and function and have generated unique NK-22 specific reagents as well as mouse strains lacking NK-22 or AHR in several immune and non-immune cell types. Therefore, we are in a unique position to directly test the impact of specific dietary supplements allegedly associated with anti-cancer activity on tumor surveillance by innate immune cells. !