4.肿瘤与免疫-逃逸免疫机制.pptxVIP

肿瘤的免疫逃逸机制Mechanism of Tumor Evasion of the Immune System;; 二十世纪五十年代后期，Thomas和Bernet基于许多实验证据和临床提出免疫监视（immune surveillance）学说，认为免疫系统能持续地监视体内出现的异常细胞，识别并摧毁它们。该学说从免疫学角度提出机体如何防治肿瘤发生的机制，并已被大量研究结果加以证实，但也存在着局限性，难以解释某些肿瘤发生机制与机体免疫系统的相互关系。;基因突变、融合或重排表达产物 细胞癌变过程中产生新的或异常的蛋白质分子 致瘤病毒的相关表达蛋白 细胞蛋白异常糖基化 隐蔽的抗原表位暴露 多种膜蛋白分子的异常聚集 胚胎抗原、分化抗原或癌基因相关蛋白的异常高表达;免疫监视对肿瘤发生和发展的作用;免疫监视对肿瘤发生认识的局限性;Relative risk of tumor in immunosuppressed kidney transplant recipients;免疫抗病毒与肿瘤关系;Role of EBV in tumorigenesis;The major effector mechanisms for tumor cell killing may be the induction of tumor cell apoptosis via specific death receptor- mediated signaling and/or secretion of cytotoxic molecules such as granzyme B or perforine (A). Several HCMV-induced escape mechanisms can be assumed in this regard. HCMV encodes or stimulates cellular antiapoptotic proteins that protect the infected tumor cells from cytotoxic agents and/or from apoptosis (B). HCMV infection leads to enhanced expression of death receptor ligands that may induce apoptosis in immune effector cells (C). HCMV-infected tumor cells secrete, for example, immune suppressive cytokines that may inhibit effector cells (D).;; 2002年Dunn和Schreiber等在“免疫监视”学说的基础上提出了肿瘤免疫编辑 (immunoediting)学说。该学说将肿瘤与机体免疫系统相互作用的过程分为三个阶段：清除期(elimination)、平衡期(equilibrium)和逃逸期(escape)。 清除期即传统意义上的免疫监视过程；平衡期是指清除期未被完全破坏的肿瘤细胞潜伏在体内，并与免疫系统相互作用处于相持状态的阶段；逃逸期指肿瘤在与免疫系统的相互作用中，经历了免疫系统的重塑(sculpt)，使肿瘤细胞可以通过修饰自身表面抗原以及改变肿瘤组织周围微环境，如分泌大量免疫抑制因子、招募免疫抑制细胞等，达到下调免疫活性细胞功能，从而逃避了免疫系统对肿瘤细胞的识别和攻击，并进行性生长的阶段。;;Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle. Each step of the Cancer-Immunity Cycle requires the coordination of numerous factors, both stimulatory and inhibitory in nature. Stimulatory factors shown in green promote immunity, whereas inhibitors shown in red help keep the process in check and reduce immune activity and/or prevent autoimmunity. Immune checkpoint proteins, such as CTLA4, can inhibit the development of an active immune response by acting primarily at