Ashwagandha supplementation enhances ovarian tumoricidal activity of NK cells

描述（由申请人提供）：卵巢癌（OVCA）是妇科癌症中病例死亡率最高的妇女致命恶性肿瘤。OVCA不同于其他恶性肿瘤，它主要在腹膜和腹腔局部播散。因此，肿瘤微环境因素在肿瘤进展和OVCA转移预防中起着至关重要的作用。先天免疫细胞是肿瘤微环境的成员，是肿瘤发生的第一反应者。然而，肿瘤通过分泌免疫抑制因子来抑制抗肿瘤免疫反应，在大多数情况下，这些免疫抑制因子将先天免疫细胞的抗肿瘤功能转变为有利于肿瘤生长的促肿瘤作用。自然杀伤（NK）细胞是先天免疫系统的一员，具有细胞毒功能，是消除生长中的肿瘤所必需的。然而，我们的初步研究表明，卵巢肿瘤进展到晚期与抑制NK细胞浸润到肿瘤附近有关。我们的初步研究进一步表明，这种肿瘤诱导的肿瘤内NK细胞浸润的抑制是通过恶性细胞表面表达的主要组织相容性复合体I类相关链A （MICA）的脱落介导的。MICA是NK细胞受体NKG2D的配体。与MICA结合后，NKG2D激活NK细胞的细胞毒活性。MICA从肿瘤表面脱落，阻止NK细胞识别肿瘤细胞，从而使肿瘤逃避NK细胞的细胞毒性作用。在我们的初步研究中，在母鸡的饲粮中添加（含或不含OVCA） Ashwagandha根粉可以抑制肿瘤的进展，降低新的OVCA病例的发生率。印度烟是一种在传统医学中用作抗压力和消炎剂的草药。拟议的研究旨在通过两个特定目的在一大批母鸡中证实这些初步观察结果。目的1将确定Ashwagandha是否能增加肿瘤内NK细胞的涌入，从而增强NK细胞的卵巢杀肿瘤作用。目的2将确定在饮食中补充Ashwagandha所需的暴露时间，以维持NK细胞的长期抗肿瘤活性。该研究的成功完成将产生宝贵的信息，并将有助于更长期的研究和/或早期临床研究，以检验Ashwagandha在增强NK细胞卵巢肿瘤功能中的作用。

DESCRIPTION (provided by applicant): Ovarian cancer (OVCA) is a fatal malignancy of women with highest case to death ratio among gynecological cancers. OVCA differs from other malignancies that it mainly disseminates locally in the peritoneal and abdominal cavity. Thus, factors in tumor microenvironment play critical roles in tumor progression as well as prevention of OVCA metastasis. Innate immune cells are members of tumor microenvironment and first responders to a developing tumor. However, tumor suppresses anti-tumor immune responses by secreting immunosuppressive factors, which in most cases, shift anti-tumor functions of innate immune cells to pro-tumor roles favoring tumor growth. Natural killer (NK) cells are a member of innate immunity with cytotoxic functions necessary to eliminate a growing tumor. However, our preliminary studies showed that progression of ovarian tumors to late stages was associated with the inhibition of NK cell infiltration to the tumor vicinity. Our preliminary studis further showed that this tumor-induced inhibition of intra-tumor NK cell infiltration was mediated by shedding of major histocompatibility complex class I related chain A (MICA) expressed on the surface of malignant cells. MICA is a ligand of NK cell receptor NKG2D. Upon binding with MICA, NKG2D activates NK cells for cytotoxic activities. Shedding of MICA by the tumor from its surface prevents NK cells to recognize the tumor cells, thus, the tumor escapes cytotoxic effects of NK cells. Dietary supplementation of hens (with or without OVCA) with Ashwagandha root powder in our preliminary study showed inhibition of tumor progression and reduced incidence of new OVCA cases. Ashwagandha is an herb used in traditional medicine as anti-stressor and inflammatory agent. Proposed study seeks to confirm these preliminary observations in a large cohort of hens by two Specific Aims. Aim 1 will determine the efficacy of Ashwagandha in increasing the influx of intra-tumoral NK cells and thus enhancing ovarian tumoricidal role of NK cells. Aim 2 will determine the length of exposure to dietary Ashwagandha supplementation required to maintain a long- term anti-tumor activities of NK cells. Successful accomplishment of the proposed study will generate noble information and will be helpful for a longer study and/or an early phase clinical study to examine the role of Ashwagandha in enhancing ovarian tumoricidal functions of NK cells.