肿瘤与免疫-肿瘤的免疫逃逸机制课件

肿瘤的免疫逃逸机制
Mechanism of Tumor Evasion of the Immune System
免疫监视和免疫编辑学说 肿瘤的免疫逃逸机制
免疫监视和免疫编辑学说
一、免疫监视
1. 免疫监视学说 2. 免疫监视对肿瘤发生和发展的影响 3. 免疫监视对肿瘤发生认识的局限性 4. 免疫抗病毒与肿瘤发生的关系
Carcinoma of the liver
20-35
Carcinoma of the skin
20-50
Carcinoma of the cervix
2.5-10
Melanoma
2.Байду номын сангаас-10
Lung
1-2
In all forms of immunodeficiency the relative risk of developing tumors in which viruses are known to play a role is greatly increased. This is the case for all those listed except cancer of the lung. The relative risks vary in different studies according to the length of follow up and the presence of cofactors such as sunlight for skin cancer.
Relative risk of tumor in immunosuppressed kidney transplant recipients
Tumor type
Approximate relative risk
Kaposi’s sarcoma
50-100
Non-Hodgkin lymphoma
25-45
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).
“免疫编辑”学说首次提出免疫系 统在与肿瘤细胞的相互作用过程中发挥 了双重作用：免疫系统一方面具有监视、 清除肿瘤的能力；另一方面，免疫系统 参与肿瘤组织周围微环境形成，促进弱 免疫原性肿瘤细胞的发生与发展。
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 the level of T cell development and proliferation (step 3). We distinguish these from immune rheostat (‘‘immunostat’’) factors, such as PDL1, can have an inhibitory function that primarily acts to modulate active immune responses in the tumor bed (step 7). Examples of such factors and the primary steps at which they can act are shown. Abbreviations are as follows: IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high-mobility group protein B1; TLR, Toll-like receptor; HVEM, herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic Tlympocyte antigen-4; PD-L1, programmed death-ligand 1; CXCL/CCL, chemokine motif ligands; LFA1, lymphocyte function-associated antigen-1; ICAM1, intracellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indoleamine 2,3dioxygenase; TGF, transforming growth factor; BTLA, B- and T-lymphocyte attenuator; VISTA, V-domain Ig suppressor of T cell activation; LAG-3, lymphocyte-activation gene 3 protein; MIC, MHC class I polypeptiderelated sequence protein; TIM-3, T cell immunoglobulin domain and mucin domain-3. Although not illustrated, it is important to note that intratumoral T regulatory cells, macrophages, and myeloid-derived suppressor cells are key sources of many of these inhibitory factors. See text and Table 1 for details.
Medicinal Research Reviews, Vol. 25, No. 2, 167-185, 2005
二、免疫编辑
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) 。
免疫抗病毒与肿瘤关系
多种病毒(HIV, HPV, EBV等)感染宿主细胞，易诱发肿瘤； 多种病毒干扰免疫识别和应答； 免疫应答限制了病毒复制，阻止潜在的致癌病毒扩散； Ｔ细胞识别肿瘤细胞中病毒表达蛋白，杀伤肿瘤； 抗淋巴细胞血清诱发的免疫抑制小鼠＋病毒感染可引起肿
瘤高发生率。
* 免疫系统功能在于阻止病毒诱发的肿瘤发生,而对非病毒诱发的肿瘤发生则无作用？ **胃癌与幽门螺杆菌（Helicobacter pylori, Hp）
免疫监视对肿瘤发生认识的局限性
裸鼠(Ｔ细胞缺陷)和抗淋巴细胞血清诱发的 免疫抑制小鼠未见肿瘤发生率增加；
免疫抑制个体(肾移植)中人类常见肿瘤发生 率不高；
致癌剂(甲基胆蒽)在SCID (Ｔ、B细胞联合缺 陷)和正常小鼠诱导肿瘤发生率无明显差异；
肿瘤抗原剂量的影响(中等剂量易发生免疫应 答现象)。
免疫监视对肿瘤发生和发展的作用
体外免疫效应细胞抗肿瘤作用； 实验动物模型显示抗肿瘤免疫的存在； 从患者中能够检测到抗肿瘤免疫应答，增
强机体免疫应答能够产生治疗效果； 肿瘤灶内免疫细胞浸润程度与预后有关； 免疫缺陷人群和免疫抑制的个体中肿瘤发
生率增高； 肿瘤在儿童和老年人更为常见； 肿瘤的自发性消退； 尸检数据表明有许多肿瘤并无临床表现。