KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden
KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden
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DOI：
10.1016/j.annonc.2020.08.2105
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发表时间：
2020-12-01
影响因子：
50.5
通讯作者：
Maugeri-Sacca, M.
中科院分区：
文献类型：
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作者：
Marinelli, D.;Mazzotta, M.;Maugeri-Sacca, M.
背景：免疫检查点抑制物(ICIS)对肺腺癌(LUAD)患者的总体生存(OS)有显著的益处。然而，无论程序性死亡配体1(PD-L1)的表达和肿瘤突变负担(TMB)如何，患者间的免疫治疗效果都具有显著的异质性。在接受化疗的LUAD患者中，Keap1突变与较短的生存期有关。我们假设Keap1共突变和互斥性的模式可以识别免疫治疗无效的LUAD患者。患者和方法：在整个MSKCC LUAD数据集中研究Keap1突变共存和躯体相互作用。共存改变对接受ICI治疗的LUAD患者的生存结果的影响在随机的II/III期杨树/橡树试验中得到了验证(基于血液的测序，bNGS队列，N=253)。三项基于组织的测序研究(罗马、MSKCC和DFCI)用于独立验证(TNGs队列，N=289)。结果：根据Keap1基因突变共现，我们发现了4个可能与免疫治疗效果降低相关的基因(Keap1、PBRM1、SMARCA4和STK11)。与共存改变的性质无关，与单一突变(SM)和野生型(WT)肿瘤相比，共存突变(CoMut)的存活率较低(bNGS队列：CoMut与SM对数列P=0.048，CoMut对WT对数列P<；0.001；TNGs队列：CoMut对SM对数列P=0.037，CoMut对WT对数列P=0.006)。COMut亚型的TMB高于WT病，合并TMB高的LUAD患者仍存在共存改变的不良意义。CoMut组和WT组在核心免疫特征、T细胞受体谱系、辅助性T细胞特征和免疫调节基因等方面存在显著的免疫基因组学差异。结论：本研究提示LUAD患者中有一部分对免疫治疗无反应且TMB较高。免疫寒冷的微环境可能是该病临床病程的原因。
Background: Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy.Patients and methods: KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study.Results: On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes.Conclusions: This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.