Shimizu Takashi, Ohkuma Ryotaro, Homma Mayumi, Nakayama Shingo, Sasaki Yosuke, Muto Satoshi, Ieguchi Katsuaki, Watanabe Makoto, Taguchi Akashi, Takayanagi Daisuke, Wada Youichiro, Horiike Atsushi, Kubota Yutaro, Ariizumi Hirotsugu, Shimokawa Masahiro, Hirasawa Yuya, Ishiguro Tomoyuki, Suzuki Risako, Iriguchi Nana, Mura Emiko, Yoshimura Kiyoshi, Tsuji Mayumi, Kiuchi Yuji, Suzuki Hiroyuki, Yamochi Toshiko
Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan.
Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical University, Tokyo, Japan.
Front Immunol. 2025 Sep 8;16:1528594. doi: 10.3389/fimmu.2025.1528594. eCollection 2025.
A prior retrospective analysis demonstrated that quantifying Programmed Cell Death Ligand 1 (PD-L1) expression using a phosphor-integrated dot (PID) score effectively predicted immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC) and other cancers. However, PD-L1 expression proved unreliable in some patients with low PD-L1 levels, highlighting the need for alternative biomarkers. A previous cohort study in NSCLC patients linked intestinal (Akk) presence to improved ICI efficacy, particularly in low PD-L1 subgroups. Here, we evaluated tumor tissue Akk expression via immunohistochemical staining as a potential biomarker for ICI response in NSCLC.
We retrospectively analyzed tumor tissues from 60 metastatic or recurrent NSCLC patients treated with ICIs. Immunohistochemical (IHC) staining was performed to assess Akk and PD-L1 expression, along with CD3 and CD68 in PD-L1-low samples. Transcriptomic profiling using RNA-sequencing was conducted on tumor samples to identify Akk-related gene expression patterns.
Tumor Akk expression showed no correlation with PD-L1 levels assessed via PID. Survival and multivariable Cox regression analyses revealed no association between Akk expression and progression-free survival (PFS) or overall survival (OS). In high PD-L1 patients, Akk status did not influence outcomes. However, among low PD-L1 patients, Akk-positive cases exhibited significantly worse PFS compared to Akk-negative cases (OS remained unchanged). Transcriptome analysis indicated that Akk positivity in low PD-L1 samples exhibited enrichment in oxidative phosphorylation and amyotrophic lateral sclerosis-related pathways and downregulation of spliceosome-associated pathways. No significant differences in tumor-infiltrating CD3+ T cells or CD68+ macrophages were observed between Akk-positive and Akk-negative tumors in the PD-L1-low group.
Tumor-associated Akk may serve as a negative predictive biomarker for ICI efficacy in NSCLC patients with low PD-L1 expression. Our findings suggest that tumor microbiota profiling, particularly targeting Akk, could refine patient stratification and therapeutic decision-making.
先前的一项回顾性分析表明，使用磷整合点（PID）评分来量化程序性细胞死亡配体1（PD-L1）的表达，可有效预测非小细胞肺癌（NSCLC）及其他癌症中免疫检查点抑制剂（ICI）的疗效。然而，在一些PD-L1水平较低的患者中，PD-L1表达被证明不可靠，这凸显了对替代生物标志物的需求。先前一项针对NSCLC患者的队列研究将肠道阿克曼菌（Akk）的存在与ICI疗效的改善联系起来，尤其是在低PD-L1亚组中。在此，我们通过免疫组织化学染色评估肿瘤组织中阿克曼菌的表达，作为NSCLC中ICI反应的潜在生物标志物。
我们回顾性分析了60例接受ICI治疗的转移性或复发性NSCLC患者的肿瘤组织。进行免疫组织化学（IHC）染色以评估阿克曼菌和PD-L1的表达，以及PD-L1低表达样本中的CD3和CD68。对肿瘤样本进行RNA测序的转录组分析，以确定与阿克曼菌相关的基因表达模式。
肿瘤阿克曼菌表达与通过PID评估的PD-L1水平无相关性。生存分析和多变量Cox回归分析显示，阿克曼菌表达与无进展生存期（PFS）或总生存期（OS）之间无关联。在高PD-L1患者中，阿克曼菌状态不影响预后。然而，在低PD-L1患者中，与阿克曼菌阴性病例相比，阿克曼菌阳性病例的PFS显著更差（OS保持不变）。转录组分析表明，低PD-L1样本中的阿克曼菌阳性表现为氧化磷酸化和肌萎缩侧索硬化相关途径的富集以及剪接体相关途径的下调。在PD-L1低表达组中，阿克曼菌阳性和阴性肿瘤之间未观察到肿瘤浸润性CD3+T细胞或CD68+巨噬细胞有显著差异。
肿瘤相关的阿克曼菌可能作为低PD-L1表达的NSCLC患者ICI疗效的阴性预测生物标志物。我们的研究结果表明，肿瘤微生物群分析，特别是针对阿克曼菌的分析，可优化患者分层和治疗决策。
