EGFR - TKI和免疫选择压力下克隆驱动新抗原丢失，这一成果由英国伦敦大学学院癌症研究所Charles Swanton研究小组经过不懈努力而取得。这一研究成果发表在2025年2月19日出版的国际学术期刊《自然》上。

该课题组研究人员追踪了一名EGFR突变肺癌患者的系统发育史，该患者接受厄洛替尼、奥西替尼、放疗和针对10个体细胞突变（包括EGFR外显子19缺失（ex19del））的个体化新肽疫苗（NPV）治疗。ex19del突变是无性系的，但很可能是在全基因组加倍（WGD）事件后出现的。在奥西替尼和NPV治疗后，在进展中的小细胞转化肝转移中发现了ex19del突变的缺失。追踪467个体细胞变异的循环肿瘤DNA分析显示，在接种疫苗前存在这种EGFR野生型克隆，并在奥西替尼/NPV治疗期间扩增。尽管系统性T细胞对疫苗靶向的ex19del新抗原有反应，但NPV未能阻止疾病进展。

肝转移通过染色体不稳定失去疫苗靶向的新抗原，并表现出不利的微环境，其特征是免疫浸润有限，CXCL9低和M2巨噬细胞水平升高。WGD后产生的新抗原比WGD前产生的新抗原更有可能在进展性肝转移中缺失，这表明优先考虑WGD前的新抗原可能会改善疫苗设计。来自TRACERx 421队列的数据提供了证据，证明WGD前突变更好地代表克隆变异，并且由于它们存在于多个拷贝数，在转移转移中不太可能丢失。这些数据强调了系统发育疾病追踪和功能性T细胞分析在了解联合治疗期间免疫逃逸机制方面的力量。

据悉，新抗原疫苗正在研究用于多种癌症，包括表皮生长因子受体（EGFR）驱动的肺癌。

附：英文原文

Title: Clonal driver neoantigen loss under EGFR TKI and immune selection pressures

Author: Al Bakir, Maise, Reading, James L., Gamble, Samuel, Rosenthal, Rachel, Uddin, Imran, Rowan, Andrew, Przewrocka, Joanna, Rogers, Amber, Wong, Yien Ning Sophia, Bentzen, Amalie K., Veeriah, Selvaraju, Ward, Sophia, Garnett, Aaron T., Kalavakur, Paula, Martnez-Ruiz, Carlos, Puttick, Clare, Huebner, Ariana, Cook, Daniel E., Moore, David A., Abbosh, Chris, Hiley, Crispin T., Naceur-Lombardelli, Cristina, Watkins, Thomas B. K., Petkovic, Marina, Schwarz, Roland F., Glvez-Cancino, Felipe, Litchfield, Kevin, Meldgaard, Peter, Sorensen, Boe Sandahl, Madsen, Line Bille, Jger, Dirk, Forster, Martin D., Arkenau, Tobias, Domingo-Vila, Clara, Tree, Timothy I. M., Kadivar, Mohammad, Hadrup, Sine Reker, Chain, Benny, Quezada, Sergio A., McGranahan, Nicholas, Swanton, Charles

Issue&Volume: 2025-02-19

Abstract: Neoantigen vaccines are under investigation for various cancers, including epidermal growth factor receptor (EGFR)-driven lung cancers1,2. We tracked the phylogenetic history of an EGFR mutant lung cancer treated with erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine (NPV) targeting ten somatic mutations, including EGFR exon 19 deletion (ex19del). The ex19del mutation was clonal, but is likely to have appeared after a whole-genome doubling (WGD) event. Following osimertinib and NPV treatment, loss of the ex19del mutation was identified in a progressing small-cell-transformed liver metastasis. Circulating tumour DNA analyses tracking 467 somatic variants revealed the presence of this EGFR wild-type clone before vaccination and its expansion during osimertinib/NPV therapy. Despite systemic T cell reactivity to the vaccine-targeted ex19del neoantigen, the NPV failed to halt disease progression. The liver metastasis lost vaccine-targeted neoantigens through chromosomal instability and exhibited a hostile microenvironment, characterized by limited immune infiltration, low CXCL9 and elevated M2 macrophage levels. Neoantigens arising post-WGD were more likely to be absent in the progressing liver metastasis than those occurring pre-WGD, suggesting that prioritizing pre-WGD neoantigens may improve vaccine design. Data from the TRACERx 421 cohort3 provide evidence that pre-WGD mutations better represent clonal variants, and owing to their presence at multiple copy numbers, are less likely to be lost in metastatic transition. These data highlight the power of phylogenetic disease tracking and functional T cell profiling to understand mechanisms of immune escape during combination therapies.

DOI: 10.1038/s41586-025-08586-y

Source: https://www.nature.com/articles/s41586-025-08586-y