Tumor-based Modulators of Antibody-Dependent Cellular Cytotoxicity (ADCC)

描述(申请人提供)：基于抗体的特异性和多功能性，单抗治疗是抗癌工具的重要组成部分。单抗的抗肿瘤作用主要来源于两个作用机制：调节信号转导和体内存活，以及诱导针对肿瘤细胞的免疫反应。某些单抗可以通过Fc受体介导的相互作用来结合免疫效应器-主要是自然杀伤(NK)细胞-诱导抗体- 依赖性细胞毒性(ADCC)。临床前和临床证据表明，ADCC在许多治疗性单抗的抗肿瘤反应中起重要作用。然而，像大多数癌症治疗方法一样，肿瘤对单抗治疗产生抵抗力。在致癌信号网络中--例如，在EGFR信号网络中--已经确定了遗传耐药决定因素，它们的调节可以基于增殖减少和细胞死亡增加而增强治疗反应--例如，EGFR靶向的小分子或单抗。然而，耐药决定因素也可能调节肿瘤对ADCC的反应。这样的决定因素还没有确定。本项目旨在阐明新的基于肿瘤的ADCC分子决定因素，以提高对单抗治疗的理解和疗效。具体目标集中在评估两种可能的耐药机制：可能促进逃避ADCC细胞毒效应的致癌信号网络；以及基于肿瘤的免疫突触形成的调节，以逃避ADCC。高通量功能基因组学筛选用于评估其敲除调控ADCC的基因。验证研究将用于确认筛选结果，随后将进行体外研究以确定ADCC调节的具体机制。动物模型研究将在体内验证那些影响ADCC的分子决定因素。整个过程的重点是发现ADCC的调节机制，以增强单抗治疗对人类恶性肿瘤的靶向治疗的疗效。 公共卫生相关性：基于其特异性和多功能性，单抗是癌症治疗的关键组成部分。该项目旨在确定肿瘤细胞如何 调节他们对抗体治疗过程中被激活的“杀手”免疫细胞的反应。总体目标是了解肿瘤细胞中的分子成分如何用于预测或增强对人类癌症单抗治疗的反应。

DESCRIPTION (provided by applicant): Monoclonal antibody therapy is an important component of the anti-cancer armamentarium, based on the specificity and versatility of antibodies. The anti-tumor effects of monoclonal antibodies are derived from two main mechanisms of action: modulating signal transduction and survival within, and inducing immune responses against tumor cells. Certain monoclonal antibodies can engage immune effectors- primarily natural killer (NK) cells-through Fc receptor-mediated interactions that induce antibody- dependent cellular cytotoxicity (ADCC). Preclinical and clinical evidence suggests that ADCC is important for anti-tumor responses for many therapeutic monoclonal antibodies. However, like most cancer therapeutics, tumors develop resistance to monoclonal antibody therapies. Genetic resistance determinants have been identified in oncogenic signaling networks-e.g., in the EGFR signaling network- whose modulation can enhance therapeutic response-e.g., EGFR-targeted small molecules or monoclonal antibodies-based on decrease in proliferation and enhanced cell death. However, it is plausible that resistance determinants could modulate tumor response to ADCC as well. Such determinants have not been identified. This project aims to elucidate novel tumor-based molecular determinants of ADCC that will enhance understanding and efficacy of monoclonal antibody therapy. The specific aims focus on assessing two putative mechanisms of resistance: oncogenic signaling networks that may promote escape from the cytotoxic effects of ADCC; and tumor-based modulation of immune synapse formation to evade ADCC. High-throughput functional genomics screening is used to assess genes whose knockdown modulates ADCC. Validation studies will be used to confirm screening results, followed by in vitro studies to identify specific mechanisms of ADCC modulation. Animal model studies will verify those molecular determinants whose modulation affects ADCC in vivo. The overall process is focused on discovering mechanisms of modulation of ADCC that enhance efficacy of monoclonal antibody therapies for the targeted treatment of human malignancies. PUBLIC HEALTH RELEVANCE: Monoclonal antibodies are critical components of cancer therapy, based on their specificity and versatility. This project aims to determine how tumor cells modulate their response to "killer" immune cells that are activated during antibody therapy. The overall goal is to understand how molecular components in tumor cells can be used to predict or enhance response to monoclonal antibody therapy in human cancer.