Modeling MIC Shedding in Prostate Cancer Progression

描述（由申请人提供）：本申请中拟定的研究旨在使用动物模型了解前列腺癌中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）在大多数上皮肿瘤（包括前列腺癌）中表达。MIC被鉴定为NKG 2D的配体，NKG 2D是一种由所有人类自然杀伤（NK）细胞和细胞毒性T细胞表达的刺激性免疫受体。MIC与NKG 2D的结合触发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用于免疫监视。研究表明，晚期癌细胞产生两种形式的MIC，表面膜结合MIC和可溶性形式MIC（sMIC）。已显示siMIC介导MIC-NKG 2D介导的抗肿瘤免疫的缺陷。前列腺癌中令人信服的临床研究已经证明，血清sMIC水平在晚期癌症中增加。目前尚不清楚sMIC是否允许较低级别的肿瘤变得更具侵袭性，或者是否进展到更具侵袭性的表型导致sMIC的产生。这项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，并确定和验证对抗肿瘤产生sMIC的策略。为了实现这一长期目标，这项拟议的研究旨在建立一个动物模型，以进一步研究前列腺癌的这些临床观察结果。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，sMIC也在其他上皮肿瘤中产生，如乳腺癌、肺癌和结肠癌，因此这项研究的结果也将在其他上皮肿瘤中产生广泛的临床意义。

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.