Purpose: Co-occurring mutations in KEAP1 and STK11KRAS have emerged as determinants of survival outcomes in non-small cell lung cancer (NSCLC) patients treated with immunotherapy. However, these mutational contexts identify a fraction of non-responders to immune checkpoint inhibitors. We hypothesized that KEAP1 wild-type tumors recapitulate the transcriptional footprint of KEAP1 mutations, and that this KEAPness phenotype can determine immune responsiveness with higher precision compared to mutation-based models. Experimental Design: The TCGA was used to infer the KEAPness phenotype and explore its immunological correlates at the pan-cancer level. The association between KEAPness and survival outcomes was tested in two independent cohorts of advanced NSCLC patients treated with immunotherapy and profiled by RNA-Seq (SU2C n=153; OAK/POPLAR n=439). The NSCLC TRACERx421 multi-region sequencing study (tumor regions n=947) was used to investigate evolutionary trajectories. Results: KEAPness-dominant tumors represented 50% of all NSCLCs and were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAPness-free cases in independent cohorts of NSCLC patients treated with immunotherapy (SU2C PFS P=0.042, OS P=0.008; OAK/POPLAR PFS P=0.0014, OS P<0.001). Patients with KEAPness tumors had survival outcomes comparable to those with KEAP1-mutant tumors. In the TRACERx421, KEAPness exhibited limited transcriptional intratumoral heterogeneity and immune exclusion, resembling the KEAP1-mutant disease. This phenotypic state occurred across genetically divergent tumors, exhibiting shared and private cancer genes under positive selection when compared to KEAP1-mutant tumors. Conclusions: We identified a KEAPness phenotype across evolutionary divergent tumors. KEAPness outperforms mutation-based classifiers as a biomarker of inferior survival outcomes in NSCLC patients treated with immunotherapy.

中文翻译：

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有害 KEAP1 突变的转录表型与免疫疗法治疗肺癌的生存结果相关


目的：KEAP1 和 STK11KRAS 的共存突变已成为接受免疫治疗的非小细胞肺癌 (NSCLC) 患者生存结果的决定因素。然而，这些突变背景识别出一小部分对免疫检查点抑制剂无反应的人。我们假设 KEAP1 野生型肿瘤重现了 KEAP1 突变的转录足迹，并且与基于突变的模型相比，这种 KEAPness 表型可以更精确地确定免疫反应。实验设计：TCGA 用于推断 KEAPness 表型并探索其在泛癌水平上的免疫学相关性。在接受免疫治疗的两个独立的晚期 NSCLC 患者队列中测试了 KEAPness 与生存结果之间的关联，并通过 RNA-Seq 进行分析（SU2C n=153；OAK/POPLAR n=439）。 NSCLC TRACERx421 多区域测序研究（肿瘤区域 n=947）用于研究进化轨迹。结果：在接受免疫治疗的 NSCLC 患者独立队列中，与无 KEAPness 病例相比，以 KEAPness 为主的肿瘤占所有 NSCLC 的 50%，并且与较短的无进展生存期 (PFS) 和总生存期 (OS) 相关 (SU2C PFS P= 0.042，OS P=0.008；橡木/杨木 PFS P=0.0014，OS P<0.001）。 KEAPness 肿瘤患者的生存结果与 KEAP1 突变肿瘤患者相当。在 TRACERx421 中，KEAPness 表现出有限的转录瘤内异质性和免疫排斥，类似于 KEAP1 突变疾病。这种表型状态发生在遗传上不同的肿瘤中，与 KEAP1 突变肿瘤相比，在正向选择下表现出共享和私有的癌症基因。 结论：我们在进化趋异的肿瘤中鉴定出了 KEAPness 表型。作为接受免疫治疗的 NSCLC 患者生存结果较差的生物标志物，KEAPness 优于基于突变的分类器。