肿瘤非同义突变与肿瘤新生抗原
在肿瘤起始,发展过程中,发生了成千上万的体细胞突变。其中大多数突变不稳定,不能获得生长优势,所以只是一过性的突变,称之为passenger mutations。少数突变可以诱导正常细胞恶变,促进肿瘤生长,对靶向药物产生耐受,称之为driver mutations。二者均可产生氨基酸改变,都称之为非同义突变(nonsynonymous mutations),产生和正常细胞不同的蛋白质。
肿瘤新生抗原(neoantigens)主要来自于非同义突变。因为肿瘤新生抗原在正常细胞不表达,理论上可以刺激更强的T细胞反应 (高亲和力的TCR,T细胞扩增,和肿瘤组织浸润淋巴细胞数量增多,因而肿瘤新生抗原疫苗和免疫检查点联用效果好 ) 。
肿瘤新生抗原研究及临床应用简史
肿瘤新生抗原发现和验证流程
虽然对于肿瘤新生抗原有各种各样的质疑(准确性,异质性等),但是对这类只有肿瘤表达的抗原的深入认识,才能让我们更好的认识我们的敌人。
简而言之:健康细胞和肿瘤细胞进行DNA测序,发现肿瘤变异序列,进而RNA测序,通过生物信息学的方法预测蛋白酶体降解的序列,以及可被MHC分子递呈的序列。
最后一步,T细胞验证实验。
肿瘤新生抗原的应用
伴随诊断:肿瘤新生抗原的丰度,证实和多种抗肿瘤药(尤其免疫检查点抑制剂)疗效相关(争论见下文)。
治疗药物:
疫苗:个性化的肿瘤新生抗原肽,RNA,DC疫苗
细胞治疗:新生抗原特异性的T细胞治疗
临床应用的争论
开始有一些肿瘤医生提出:肿瘤新生抗原/肿瘤突变负荷(TMB)太多时,免疫检查点抑制剂疗效并不好。
当突变负荷增加到一定程度(窗口研究需要科学家们努力),会严重增加亚克隆的数量,导致极强的肿瘤异质性和肿瘤逃逸,产生差的临床结果。
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