肿瘤新生抗原研究简史及争论

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）。

 

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肿瘤新生抗原研究及临床应用简史

 

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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。

 

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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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