Modeling MIC Shedding in Prostate Cancer Progression

描述（由申请人提供）：本申请拟进行的研究旨在通过动物模型了解前列腺癌的特异性抗肿瘤免疫。转化诱导的主要组织相容性（MHC） I链相关分子（MIC）在大多数上皮性肿瘤中表达，包括前列腺癌。MIC被鉴定为NKG2D的配体，NKG2D是一种刺激免疫受体，由所有人类自然杀伤细胞（NK）和细胞毒性T细胞表达。MIC与NKG2D结合可触发NK细胞并增强T细胞抗肿瘤免疫。MIC在转化细胞上的表面表达被提出用于标记新生肿瘤以进行免疫监视。研究表明，晚期癌细胞产生两种形式的MIC，表面膜结合的MIC和可溶性形式的MIC （sMIC）。研究表明，siMIC介导MIC-NKG2D介导的抗肿瘤免疫缺陷。令人信服的前列腺癌临床研究表明，晚期癌症患者血清sMIC水平升高。目前尚不清楚sMIC是否允许低级别肿瘤变得更具侵袭性，或者是否向更具侵袭性表型的进展导致sMIC的产生。本研究的长期目标是描述sMIC水平与前列腺癌进展之间的关系，并确定和验证对抗sMIC肿瘤产生的策略。为了实现这一长期目标，本研究拟建立动物模型，进一步研究这些临床观察结果在前列腺癌中的应用。这项研究的结果可能对前列腺癌的治疗有直接的临床意义。此外，由于研究表明，其他上皮性肿瘤如乳腺癌、肺癌和结肠癌也会产生sMIC，因此本研究的结果在其他上皮性肿瘤中也将具有广泛的临床意义。

DESCRIPTION (provided by applicant): The proposed research in this application is aimed at understanding a specific anti-tumor immunity in prostate cancer using animal models. The transformation-induced major histocompatibility (MHC) I chain-related molecule (MIC) is shown to be expressed on most epithelial tumors, including prostate carcinoma. MIC is identified as a ligand for NKG2D, a stimulatory immune receptor expressed by all human natural killer (NK) and cytotoxic T cells. Engagement of MIC to NKG2D triggers NK cell and augments T cell anti-tumor immunity. Surface expression of MIC on transformed cells is proposed to mark nascent tumors for immune surveillance. Studies have shown that advanced cancer cells produce two forms of MIC, the surface membrane-bound MIC and the soluble form of MIC (sMIC). It has been shown that siMIC mediates deficiency in MIC-NKG2D mediated anti-tumor immunity. Compelling clinical studies in prostate cancer have demonstrated that levels of serum sMIC increase in advanced cancers. It is unknown whether sMIC allows a lower grade tumor to become more aggressive or whether the progression to a more aggressive phenotype causes the production of sMIC. The long-term goal of this proposed research is to delineate the relationship between levels of sMIC and prostate cancer progression and to define and validate strategies to counteract tumor production of sMIC. To achieve this long-term goal, this proposed research aims specifically at establishing an animal model to further study these clinical observations in prostate cancer. Outcomes from this proposed research would potentially have direct clinical implication for treatment of prostate cancer. Furthermore, as studies have shown that sMIC was also produced in other epithelial tumors, such as breast, lung, and colon cancers, the outcomes of this proposed research will also have broad clinical implications in other epithelial tumors.