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肿瘤免疫学

编辑

肿瘤免疫学是生物学的一个跨学科分支，研究的是理解免疫系统在肿瘤进展和发展中的作用；最为著名的应用是癌症免疫疗法，它利用免疫系统作为肿瘤的治疗手段。肿瘤免疫监测和免疫编辑是基于预防肿瘤在动物系统中发展和人类肿瘤免疫识别靶标的鉴定。

1 定义编辑

肿瘤免疫学是生物学的一个跨学科分支，研究免疫系统在肿瘤发展中的作用；最为著名的应用是癌症免疫疗法，即免疫系统用于治疗肿瘤。[1][2] 肿瘤免疫监测是布尔内特（Burnet）和托马斯（Thomas）在1957年提出的一个理论，他们提出淋巴细胞在识别和消除不断出现的新生转化细胞中充当哨兵。[3][4] 肿瘤免疫监测似乎是一个重要的宿主保护过程，它通过抑制肿瘤发生和维持正常的细胞内环境平衡来降低肿瘤发生率。[5]也有人提出，免疫监测主要是作为肿瘤免疫编辑的一个更普遍过程的组成部分。[3]

2 肿瘤抗原编辑

肿瘤可表达被免疫系统识别的肿瘤抗原，并可诱导免疫反应。[6]这些肿瘤抗原要么是TSA(肿瘤特异性抗原)，要么是TAA(肿瘤相关抗原)。[7]

肿瘤特异性抗原是仅出现在肿瘤细胞中的抗原。[7]TSAs可能是人乳头瘤病毒E6和E7蛋白等癌病毒的产物，发生在宫颈癌中，或EBV的EBNA-1蛋白，发生在Burkitt的淋巴细胞中。 [8][9] TTSA的另一个例子是突变的癌基因(如ras)和抑癌基因(如p53)的异常产物。 [10]

肿瘤相关抗原存在于健康细胞中，但由于某些原因，它们也存在于肿瘤细胞中。[7]然而，它们在表达的数量、地点或时间周期上有所不同。[11]癌胚抗原是由胚胎细胞和肿瘤表达的肿瘤相关抗原。[12]癌胚抗原的例子有由肝细胞癌产生的甲胎蛋白，或发生在卵巢癌和结肠癌中的癌胚抗原。[13][14] 更多的肿瘤相关抗原是HER2/neu、EGFR或MAGE-1。[15][16][17]

3 肿瘤免疫编辑编辑

肿瘤免疫编辑是免疫系统与肿瘤细胞相互作用的过程，它包括三个阶段:消除、平衡和逃逸，这些阶段通常被称为肿瘤免疫编辑的“三个Es”。适应性免疫系统和先天免疫系统都参与免疫编辑。[18]

在消除阶段，免疫反应导致肿瘤细胞的破坏，从而导致肿瘤抑制。然而，一些肿瘤细胞可能获得更多的突变，改变它们的特征并逃避免疫系统。这些细胞可能进入平衡阶段，在此阶段，免疫系统不能识别所有的肿瘤细胞，但同时肿瘤不会生长。这种情况可能导致逃逸期，在此期间肿瘤获得对免疫系统的支配，开始生长并建立免疫抑制环境。[19]

由于免疫编辑的结果，随着时间的推移，对免疫系统反应较弱的肿瘤细胞克隆在肿瘤中获得优势，同时被识别的细胞被消除这一过程可能被认为类似于达尔文进化论，在达尔文的进化论中，含有原癌基因或免疫抑制突变的细胞存活下来，将它们的突变传递给子细胞，子细胞本身可能发生突变并承受进一步的选择性压力，这导致肿瘤由免疫原性降低的细胞组成，并且很难消除。[19]这一现象被证明是癌症患者免疫疗法的结果。[20]

4 肿瘤逃避免疫反应的机制编辑

肿瘤细胞已经发展出各种机制来逃避免疫监视。

CD8+细胞毒性T细胞是抗肿瘤免疫的基础细胞。它们的TCR受体能识别由MHC I类呈递的抗原，当与之结合时，Tc细胞触发其细胞毒性活性。MHC I出现在所有有核细胞的表面，然而，一些癌细胞降低了MHC I的表达，并避免被细胞毒性T细胞检测到。[21]这可以通过MHCI基因突变，或通过降低对干扰素γ(影响MHCI的表面表达)的灵敏度来实现。[21][22] 另一方面，MHC I的完全丧失是自然杀伤细胞的触发因素。因此，肿瘤细胞保持MHC I [21]的低表达。逃避细胞毒性T细胞的另一种方法是停止表达细胞毒性T细胞共刺激所必需的分子，如CD80或CD86。[23][24]

肿瘤细胞通过在其表面表达FasL，可以通过FasL-Fas相互作用诱导T淋巴细胞凋亡。[25]

此外，肿瘤细胞可以通过接触依赖性或独立性刺激诱导调节性T细胞的产生。在一个健康的组织中，功能正常的调节性T细胞对维持自我耐受性至关重要。然而，在肿瘤中，调节性T细胞形成免疫增强的微环境。[26]

5 肿瘤免疫学和化学疗法编辑

奥贝德（Obeid）等人，[27]研究了如何诱导免疫原性癌细胞死亡，应该成为癌症化疗的重点。他推断，免疫系统将能够通过“旁观者效应”在根除化疗耐药的癌细胞中发挥作用。[28][29][30][2] 然而，关于免疫反应是如何被触发来对抗垂死的肿瘤细胞，仍需要广泛的研究。[2][31]

该领域的专业人员假设“凋亡细胞的死亡是免疫原性较差的，而坏死细胞的死亡是真正的免疫原性的”。[32][33][34] 这可能是因为癌症细胞通过坏死细胞死亡途径被消灭，而炎症反应刺激触发树突状细胞成熟，从而引发免疫反应。[35][36] 另一方面，细胞凋亡与质膜内的微小变化有关，使得死亡细胞对吞噬细胞有吸引力。[37]然而，许多基于动物的研究表明，与坏死细胞相比，用凋亡细胞接种疫苗在引发抗肿瘤免疫反应方面具有优势。[38][39][40][41][42]

因此奥贝德（Obeid）等人[27]提出，化疗期间癌细胞死亡的方式至关重要。蒽环类化疗药物形成一个有益的免疫原性环境。研究人员报告说，鼓励通过摄取这种药物和表达树突状细胞呈递的抗原来杀死癌细胞，产生T细胞免疫反应，从而使肿瘤缩小。因此，激活杀死肿瘤的T细胞对免疫治疗的成功至关重要。[2][43]

然而，患有免疫抑制的晚期癌症患者让研究人员陷入了如何激活t细胞的两难境地。宿主树突状细胞反应和摄取肿瘤抗原以呈现给CD4+和CD8+ T细胞的方式是治疗成功的关键。[2][44]

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