HTS for the discovery of activators of NK cell cytotoxicity

摘要 自然杀伤（NK）细胞是能够杀死恶性细胞而没有抗原特异性杀伤的淋巴细胞。 受体识别由于这种性质，NK细胞已被用于过继免疫细胞治疗， 各种恶性肿瘤尽管在血液系统恶性肿瘤方面取得的成功有限，但NK细胞的治疗潜力 用于癌症的细胞疗法已经受到NK细胞的不足的细胞毒性活性的限制，特别是对于实体瘤， 肿瘤的由于NK细胞特异性靶向癌细胞并避免杀死正常细胞的能力， 假设增强NK细胞的细胞毒活性可导致NK细胞疗法的功效增强 治疗癌症由于调节NK细胞细胞毒活性的分子介质仍没有完全表征，我们 将进行小分子高通量化合物库筛选，以鉴定NK细胞的新介质 细胞毒活性这项工作的目的是确定可以进一步开发的小分子， 治疗目的，以及揭示重要的探针，阐明机制的见解，NK细胞 这些活动可能有助于今后采取有针对性的办法。在第一个目标中，我们将鉴定出 通过不同的300k小分子集合的HTS增强NK细胞对卵巢癌细胞的杀伤。 在第二个目标中，将在一系列次级测定中测试初级命中，以鉴定最多的 很有希望的热门歌曲最有希望的命中将在体外和体内进行生物学表征。它 希望这项工作将导致确定有前途的方法，以改善NK细胞治疗 for cancer癌症patients病人.

Abstract Natural killer (NK) cells are lymphocytes that are capable of killing malignant cells without antigen-specific receptor recognition. Due to this property, NK cells have been utilized for adoptive immune cell therapy for a variety of malignancies. Despite limited success for hematologic malignancies, the therapeutic potential of NK cell therapy for cancer has been limited by the insufficient cytotoxic activity of NK cells particularly for solid tumors. Due to the ability of NK cells to specifically target cancer cells and avoid killing of normal cells, we hypothesize that enhancing the cytotoxic activity of NK cells can lead to enhanced efficacy of NK cell therapies for cancer. As the molecular mediators regulating NK cell cytotoxic activity are still not fully characterized, we will conduct a small molecule high throughput compound library screen to identify novel mediators of NK cell cytotoxic activity. The purpose of this work is to identify small molecules that can be further developed for therapeutic purposes as well as to reveal important probes to elucidate mechanistic insights into NK cell activity that may enable future targeted approaches. In the first aim, we will identify compounds that enhance NK cell killing of ovarian cancer cells through a HTS of a diverse 300k small molecule collection. In the second aim, the primary hits will be tested in a series of secondary assays to identify the most promising hits. The most promising hits will then undergo biological characterization in vitro and in vivo. It is hoped that this work will lead to the identification of promising approaches to improve NK cell therapy for cancer patients.