APOBEC-related mutagenesis and neo-peptide hydrophobicity: implications for response to immunotherapy
APOBEC-related mutagenesis and neo-peptide hydrophobicity: implications for response to immunotherapy
复制标题
DOI：
10.1080/2162402x.2018.1550341
复制
发表时间：
2019-01-01
期刊：
影响因子：
7.2
通讯作者：
Kurzrock, Razelle
中科院分区：
文献类型：
--
作者：
Boichard, Arnelie;Pham, Timothy, V;Kurzrock, Razelle
肿瘤相关新抗原是突变的肽，其允许免疫系统将受影响的细胞识别为外来物。携带过度突变负荷的细胞通常会产生耐受机制。PD-L1/PD-1检查点免疫疗法是克服这些保护性信号并诱导肿瘤缩小的非常有前途的方法。然而，驱动这些有益反应的新抗原的性质仍不清楚。在这里，我们表明，APOBEC相关的诱变-抗病毒免疫和内源性核酸编辑之间的十字路口的机制-增加新肽疏水性（免疫原性的一个特征），如通过计算机计算和TCGA泛癌症队列所证明的，其中APOBEC相关的诱变也与免疫标记物表达密切相关。此外，在99例不同癌症患者的队列中，APOBEC相关诱变与免疫治疗反应相关，并且这种相关性与肿瘤突变负荷（TMB）无关。结合APOBEC相关的诱变估计和TMB导致更大的预测能力比单独的参数。基于这些结果，有必要进一步研究APOBEC相关诱变作为对抗癌检查点阻断的应答标志物。
Tumor-associated neo-antigens are mutated peptides that allow the immune system to recognize the affected cell as foreign. Cells carrying excessive mutation load often develop mechanisms of tolerance. PD-L1/PD-1 checkpoint immunotherapy is a highly promising approach to overcome these protective signals and induce tumor shrinkage. Yet, the nature of the neo-antigens driving those beneficial responses remains unclear. Here, we show that APOBEC-related mutagenesis - a mechanism at the crossroads between anti-viral immunity and endogenous nucleic acid editing - increases neo-peptide hydrophobicity (a feature of immunogenicity), as demonstrated by in silico computation and in the TCGA pan-cancer cohort, where APOBEC-related mutagenesis was also strongly associated with immune marker expression. Moreover, APOBEC-related mutagenesis correlated with immunotherapy response in a cohort of 99 patients with diverse cancers, and this correlation was independent of the tumor mutation burden (TMB). Combining APOBEC-related mutagenesis estimate and TMB resulted in greater predictive ability than either parameter alone. Based on these results, further investigation of APOBEC-related mutagenesis as a marker of response to anti-cancer checkpoint blockade is warranted.