HLA-G蛋白在肿瘤组织及患者血清中的表达及其在肿瘤免疫逃逸中的作用

 随着对HLA-G蛋白作用机制的深入了解,越来越多的研究发现HLA-G与肿瘤免疫密切相关。大量研究显示在肿瘤患者的血浆、肿瘤组织中均可检测到HLA-G蛋白、mRNA的表达。     

非经典HLA—I类分子HLA—G在肿瘤免疫逃逸中的作用

HLA－G是非经典的HLA－I类基因，其编码产物的组织分布有限，主要分布在母胎组织的接触界面，在一些肿瘤中也有分布。多态性相对不明显，可通过与杀伤细胞抑制受体（KIR）结合，发挥抑制NK细胞和T细胞的效应。     

肿瘤免疫逃逸作用机制及在食管癌中的研究进展

肿瘤免疫逃逸对于肿瘤的存活和进展至关重要。肿瘤细胞可通过募集抑制性免疫细胞及分子来抑制抗肿瘤免疫应答,导致肿瘤逃逸。食管癌患者的病死率居于世界肿瘤致死疾病的第6位,尽管在诊断和治疗方面取得了一定进展,但其预后依然较差。通过对食管癌免疫逃逸机制的探索,可以为食管癌治疗提供新思路。本文就肿瘤免疫逃逸相关因子作用机制及在食管癌中的研究进展做一综述。      

HLA—G与肿瘤关系研究

HLA—G是一种非经典人类白细胞抗原。近年研究认为HLA—G作为免疫耐受分子，在肿瘤免疫逃逸中可能具有重要作用。现综述HLA—G的基因结构特点、在不同肿瘤中的表达情况及其临床意义和目前研究存在的问题。     

HLA-G与肿瘤免疫逃逸

HLAG是一种非经典的HLAI类抗原。在人类黑色素瘤、乳腺癌、结肠癌、胰腺癌、膀胱癌、肾癌和肺癌中可表达HLAG。HLAG可以通过抑制NK细胞、CTL细胞等效应细胞的作用，改变机体细胞因子分泌的模式来抑制机体的肿瘤免疫反应，使肿瘤细胞发生免疫逃逸而得以生存发展。     

HLA-G与肿瘤免疫逃逸作用

人白细胞抗原（human leukocyte antigen，HLA）是位于人第6号染色体短臂上的一群高度多态性的紧密连锁基因群，HLA—G属于非经典HLA—Ⅰ类分=产（HLA—Ⅰb，HLA—G、E、F），是惟一表达于母胎界面滋养层的HLA—Ⅰ类基因，参与母胎免疫耐受的形成。但是在肿瘤微环境中，肿瘤细胞产生的HLA—G可以结合NK和T细胞表面的杀伤细胞抑制受体（killing inhibitory receptor，KIR），强烈抑制T细胞和NK细胞对肿瘤靶细胞的识别、杀伤等活性，造成类似妊娠母胎界面的免疫耐受状态，形成一条新的肿瘤逃逸途径。     

肿瘤免疫逃逸机制研究新进展

机体对肿瘤的免疫应答反应处于低能状态,从而使肿瘤逃避免疫监视 而发生、发展。肿瘤可通过多条途径使机体处于免疫功能低下或耐受状,包括：干扰树突状细胞的抗原提呈、阻碍T细胞的活化及免疫应答、自身抗原表达的异常、抗凋亡因子的作用、产生有利其生长的微环境等。对肿瘤免疫逃逸机理的研究有助于人们发找和设计新的肿瘤免疫治疗方法和途径。     

Tapasin和HLA Ⅰ类分子在人卵巢癌中的表达及相关性

[目的]通过检测tapasin和HLA Ⅰ类分子在人卵巢癌中的表达,分析两者相关性,进而探讨卵巢癌的机体免疫逃逸机制.[方法]采用免疫组化SP法检测了53例卵巢癌、40例卵巢良性上皮瘤、30例正常卵巢组织中的tapasin和HLA Ⅰ类分子的表达.[结果](1)卵巢癌中HLA Ⅰ类分子的表达显著低于良性上皮瘤及正常卵巢组织(P<0.001),且卵巢癌中的HLA Ⅰ类分子的表达水平与FIGO分期有关(P<0.05).(2)tapasin在卵巢癌中呈现低表达,且其表达水平与卵巢癌中HLA Ⅰ类分子异常表达呈正相关(r=0.507,P<0.001).[结论](1)人卵巢癌细胞低表达HLA Ⅰ类分子可能是卵巢癌机体免疫逃逸机制之一.(2)人卵巢癌低表达HLAⅠ分子可能与tapasin低表达有关.     

非经典HLA-Ⅰ类分子HLA-G在肿瘤免疫逃逸中的作用

HLA-G是非经典的HLA-Ⅰ类基因，其编码产物的组织分布有限，主要分布在母胎组织的接触界面，在一些肿瘤中也有分布。多态性相对不明显，可通过与杀伤细胞抑制受体(KIR)结合，发挥抑制NK细胞和T细胞的效应。     

非经典HLA-Ⅰ类分子HLA-G在肿瘤免疫逃逸中的作用

HLA G是非经典的HLA Ⅰ类基因 ,其编码产物的组织分布有限 ,主要分布在母胎组织的接触界面 ,在一些肿瘤中也有分布。多态性相对不明显 ,可通过与杀伤细胞抑制受体 (KIR)结合 ,发挥抑制NK细胞和T细胞的效应。     

树突状细胞功能缺陷与肿瘤免疫逃逸

树突状细胞（DC）是功能强大的专职抗原提呈细胞，是机体免疫的始动者。近年来发现肿瘤及其微环境通过多种途径减少肿瘤患者体内DC的数量并可抑制DC的成熟，从而下调或抑制其抗原提呈及免疫起始功能，且可以诱导调节性DC的产生，介导免疫耐受，最终实现逃避机体免疫监视及免疫清除的目的。     

Antigenic variation in cancer metastasis: immune escape versus immune control

Summary Antigenic variation in cancer metastasis was observed in a syngeneic murine tumor system consisting of a low metastatic parental tumor line (derived from a methylcholanthrene-induced DBA/2 T lymphoma, Eb), a high metastatic spontaneous variant thereof (ESb), and a low metastatic revertant from ESb (ESb-M). All three lines expressed tumor-associated transplantation antigens (TATA) which elicited specific T cell-mediated antitumor immune reactions in the host. The strongest host response was elicited upon intradermal inoculation. It could be followed by (a) the infiltration of the locally growing tumor by host cells, such as lymphocytes and macrophages, (b) the establishment of specific systemic antitumor immunity, (c) the generation of immune cells capable of transferring protective antitumor immunity into a normal syngeneic recipient, and (d) the generation of tumor specific cytotoxic T lymphocytes (CTL).Anti-TATA CTL were used as typing reagents to investigate the stability or variability in the TATA expression by cloned tumor cell lines. Antigenic variability in the TATA expression was seen under various conditions: (a) clone-dependent variation in the sensitivity to anti-TATA CTL lysis upon prolonged growth in tissue culture, (b) qualitative change in the TATA (TATA₁ TATA₂) upon successive i.p. transplantation of the parental Eb tumor line and, (c) generation of TATA negative immune escape variants (TATA₂ TATA^-) during metastasis formation from a s.c. site.The relative inefficiency of specific immunization procedures against ESb was found to be due to the effective generation of TATA negative variants by this highly metastatic tumor. The balance between immune control and immune escape could be influenced to the advantage of the host by some means, for instance optimizing the route of antitumor-immune sensitization or by infusion of allogeneic but H-2 identical antitumor-immune T cells. Such immune cells recognized the tumor via minor histocompatibility antigens and thus circumvented the need of TATA recognition. Finally, manipulations at the cell surface of the highly malignant ESb tumor such as those introduced in the ESb-M variant were found to dramatically effect its metastatic potential.     

Immune microenvironment profiles of tumor immune equilibrium and immune escape states of mouse sarcoma

Cancer immunoediting consists of three distinct phases: elimination, equilibrium and escape. Here, for the first time, we investigated the immune microenvironment profiles of tumor immune equilibrium and immune escape states in 3′-methylcholanthrene-induced murine sarcoma model. Our study indicates the relative balance of monocytic MDSCs and antitumor immunity cells (especially CTLs, NK cells and γδT cells) may involve in maintaining tumor cells in a state of immune-mediated dormancy. In addition, high percentages of Treg cells and PMN-MDSCs are associated with the tumor immune escape state – mice with progressing sarcomas. In summary, the relative balance of immune effector cells and suppressive populations in the tumor microenvironment may involve in determining the fate of tumors.     

HLA-G in B-chronic lymphocytic leukaemia: clinical relevance and functional implications

HLA-G appears to be involved in regulatory functions counteracting the cellular immune response of T and NK cells by several pathways. We here summarize the HLA-G expression patterns in leukaemia with emphasis on the clinical relevance of this expression for disease progression. Especially in patients with B-chronic lymphocytic leukaemia (B-CLL) the HLA-G expression on B-CLL cells was strongly associated with a reduced treatment-free survival. The corresponding immunological parameters point to a broad immunosuppression in these patients. Thus, HLA-G seems to contribute to the impaired immune response in B-CLL supporting disease progression.     

恶性肿瘤的代谢与免疫逃逸

恶性肿瘤的发生发展意味着肿瘤细胞适应了不利的环境。肿瘤细胞代谢往往降低线粒体活性和氧化磷酸化过程,在很大程度上依赖有氧糖酵解产生能量。这特定的新陈代谢造成肿瘤微环境的变化,帮助肿瘤细胞得以生存、转移及免疫逃逸,而免疫逃逸包括抑制和阻断肿瘤的免疫反应。这一效应通过许多机制实现,包括肿瘤代谢过程及代谢产物对免疫系统直接和间接的抑制和阻断作用。     

HLA-G蛋白在垂体瘤中的表达及意义

目的：探讨垂体瘤中HLA-G基因编码产物的表达情况及临床病理意义。方法：应用免疫组织化学技术检测64例非侵袭性垂体瘤、8例侵袭性垂体瘤、13例复发垂体瘤、8例正常脑组织中HLA-G蛋白的表达情况。结果：8例正常脑组织HLA-G蛋白无阳性表达,64例非侵袭垂体瘤中HLA-G蛋白表达无强阳性表达,阳性表达率为25.0%,阳性信号存在于胞质中,与正常对照组比较阳性率差异有统计学意义（P〈0.05）;而8例侵袭性垂体瘤中HLA-G蛋白表达全部为阳性,强阳性率为83.3%（7/8）;13例复发垂体瘤中HLA-G蛋白表达全部为阳性,强阳性率为72.4%（9/13）。侵袭性垂体瘤及复发垂体瘤中HLA-G蛋白表达与正常对照组及非侵袭性垂体瘤比较皆有显著性差异（P〈0.01）。结论：垂体瘤的发生发展中存在HLA-G基因的过量表达现象,其阳性表达与垂体瘤的侵袭性和预后相关。