An EGFR L858R mutation identified in 1862 Chinese NSCLC patients can be a promising neoantigen vaccine therapeutic strategy.
An EGFR L858R mutation identified in 1862 Chinese NSCLC patients can be a promising neoantigen vaccine therapeutic strategy.
复制标题
DOI：
10.3389/fimmu.2022.1022598
复制
发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
本研究旨在开发一种针对中国人非小细胞肺癌(NSCLC)突变衍生新抗原的疫苗。对1862例中国非小细胞肺癌患者进行了1021基因靶向测序的队列研究。用OptiTypeV1.0进行HLA分型，用netMHCpanV4.0预测新抗原。使用LOHLA算法推断HLALOH，并基于我们的面板数据通过计算非同义词的总数来量化TMB。利用TCGA数据，用CiberSort软件估算不同EGFR突变亚型的总代谢能。人类白细胞抗原A*11：01(42.59%)为第一位等位基因，人类白细胞抗原A*33：03(12.94%)为第12位等位基因。EGFR L858R是最常见的基因变异(22.61%)。EGFR L858R与HLA-A*33：03的结合亲和力(IC50 MT=22.9 nM)和共享频率(2.93%)最佳。在随后对EGFR突变亚型免疫学特征的进一步分析中，在我们的人群中发现了63.1%的人类白细胞抗原杂合性缺失(HLALOH)和0.37%(7/1862)的B2M异常，两者都与EGFR突变亚型没有显著相关性，提示EGFR L858R的抗原提呈过程涉及到HLA LOH和B2M机制。利用我们的研究小组对肿瘤突变负荷(TMB)进行了研究，结果表明，与其他EGFR突变亚型相比，EGFR L858R的TMB最低。此外，对来自癌症基因组图谱(TCGA)数据的22种免疫细胞类型的分析表明，EGFR L858R与CD8 T细胞水平低、CD4记忆T细胞激活和巨噬细胞M2水平升高相关，表明肿瘤微环境(TME)受到抑制。我们的研究证实，EGFR L858R新抗原有可能在HLAA*33：03的非小细胞肺癌患者中产生肿瘤疫苗。在靶向治疗或免疫检查点抑制剂(ICIS)治疗失败后，新抗原疫苗可能成为EGFR L858R亚群的有效挽救方案。
This study aimed to develop a vaccine that targets mutation-derived neoantigen in Chinese non-small-cell lung cancer (NSCLC). A cohort of 1862 Chinese NSCLC patients who underwent targeted sequencing with a 1021-gene panel was investigated. HLA typing was done using OptiType v1.0 and neoantigens were predicted by netMHCpan v4.0. HLA LOH was inferred using the lohhla algorithm and TMB were quantified by counting the total number of non-synonymous ones based on our panel data. CIBERSORT was utilized to estimate the TME in different EGFR mutant subtype by using TCGA data. HLA-A*11:01(42.59%) was the top one allele and HLA-A*33:03(12.94%) ranked 12th. EGFR L858R (22.61%) was the most prevalent gene variant. The binding affinity (IC50 MT = 22.9 nM) and shared frequency (2.93%) of EGFR L858R in combination with HLA-A*33:03 were optimal. In a subsequent further analysis on immunological features of EGFR mutant subtypes, 63.1% HLA loss of heterozygosity LOH (HLA LOH) and 0.37% (7 of 1862) B2M aberrations were found in our population, both had no significant association with EGFR mutant subtypes suggesting that the process of antigen presentation involved HLA LOH and B2M mechanisms in EGFR L858R is working. Tumor mutation burden (TMB) was investigated by utilizing our panel and showed that EGFR L858R had the lowest TMB compared with other EGFR mutant subtypes. In addition, analysis of 22 immune cell types from The Cancer Genome Atlas (TCGA) data showed EGFR L858R was correlated with low level of CD8 T cells, activated CD4 memory T cells and elevated level of macrophage M2 suggesting an inhibited tumor microenvironment (TME). Our study identified that EGFR L858R neoantigen had the potential to generate cancer vaccines in NSCLC patients with HLA A*33:03. The neoantigen-based vaccines may become an effective salvage regimen for EGFR L858R subgroup after targeted therapy or immune checkpoint inhibitors (ICIs) failure.