{"title":"Impact of Sequential Ramucirumab Plus Docetaxel After PD-1 Inhibitors on Anti-PD-1 Antibody-Bound T-Cell Dynamics and Clinical Outcomes","authors":"Kinnosuke Matsumoto, Yujiro Naito, Takayuki Shiroyama, Motohiro Tamiya, Kazumi Nishino, Akihiro Tamiya, Kyoichi Okishio, Yuhei Kinehara, Tomoki Kuge, Masahide Mori, Shingo Satoh, Hidekazu Suzuki, Satoshi Tetsumoto, Toshie Niki, Yasuhiko Suga, Akio Osa, Toshiyuki Minami, Shohei Koyama, Yoshito Takeda, Nobuyuki Takakura, Atsushi Kumanogoh","doi":"10.1111/cas.70336","DOIUrl":"10.1111/cas.70336","url":null,"abstract":"<p>Ramucirumab plus docetaxel (RAM+DOC) demonstrates clinical activity after programmed cell death-1 (PD-1) inhibitors in advanced non-small cell lung cancer (NSCLC); however, the underlying mechanisms remain unclear. We aimed to evaluate clinical efficacy and explore immunologic dynamics and benefit-associated biomarkers. Patients treated with RAM+DOC after PD-1 inhibitors were enrolled in a multicenter prospective cohort. Anti-PD-1 antibody bound (IgG4<sup>+</sup>) T-cell subsets were measured at baseline (T0) and after 2–3 cycles (T1), reflecting residual anti-PD-1 antibody binding on circulating T cells. T1/T0 ratios of immune subsets were calculated to assess dynamics. Landmark analyses at T1 evaluated associations with progression-free survival (PFS) and overall survival (OS). Prognostic biomarkers were assessed at baseline. Among 27 evaluable patients, the objective response rate was 37.0%, median PFS 5.1 months, and OS 10.4 months. RAM + DOC responders had higher IgG4<sup>+</sup>CD8<sup>+</sup> T-cell and lower IgG4<sup>+</sup> Treg T1/T0 ratios (both <i>p</i> < 0.001). Higher IgG4<sup>+</sup>CD8<sup>+</sup> ratios were associated with longer landmark PFS (<i>p</i> = 0.002) and OS (<i>p</i> = 0.016) and were inversely correlated with IgG4<sup>+</sup> Treg ratios (<i>p</i> = 0.008). Among the baseline factors, high IgG4<sup>+</sup>CD8<sup>+</sup> Temra conferred survival benefits (OS, not reached vs. 8.2 months; <i>p</i> = 0.006), and low vascular endothelial growth factor (VEGF)-C levels were associated with longer OS (not reached vs. 8.5 months, <i>p</i> = 0.044). Both variables remained independent prognostic factors of PFS and OS in multivariable analysis. Our findings suggest that sequential strategy administering RAM+DOC during persistent binding of anti–PD-1 antibody to T cells may be beneficial. IgG4<sup>+</sup>CD8<sup>+</sup> Temra and VEGF-C levels at RAM+DOC initiation may serve as biomarkers of survival benefit.</p><p><b>Trial Registration:</b> UMIN-Clinical Trials Registry (UMIN000050478)</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 4","pages":"929-942"},"PeriodicalIF":4.3,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146094448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting Wnt3a and Loxl2 Synergistically Induces Ferroptosis in Liver Cancer Stem Cells and Suppresses Tumorigenesis","authors":"Guanghui Ren, Qingwei Cong, Jing Wang, Wenyue Gao, Yunpeng Guan, Lianxin Zhu, Ying Zhu","doi":"10.1111/cas.70309","DOIUrl":"10.1111/cas.70309","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) has a poor prognosis and high mortality. Ferroptosis, an iron-dependent regulated cell death process, is implicated in cancer development and treatment. Wnt signaling and lysyl oxidase (Lox) family members are associated with ferroptosis. This study investigates how Wnt3a and/or Loxl2 knockdown affects liver cancer stem cells (LCSCs) and orthotopic tumor growth in mice, and explores the role of ferroptosis-related genes. Bioinformatics identified ferroptosis- and HCC-associated differentially expressed genes (DEGs) correlated with Wnt3a/Loxl2. LCSCs sorted from Hep3B were transduced with lentivirus for gene knockdown. Ferroptosis markers and DEG expression were analyzed. Wnt3a/Loxl2 knockout mice were generated using CRISPR-Cas9, and orthotopic tumor models were established. Tumor inhibition rates, ferroptosis-related indicators, and DEG expression were assessed. 199 ferroptosis-related DEGs were identified in HCC; ZEB1 was selected as a key gene via PPI analysis. Wnt3a/Loxl2 knockdown increased Fe<sup>2+</sup> and MDA, and decreased GSH, most evidently in double-knockdown cells. In vivo, single- and double-knockout groups showed suppressed tumor growth, with inhibition rates of 51%, 71%, and 93%, respectively. Tumor tissues exhibited similar ferroptosis marker changes. ZEB1 was upregulated in both cellular and animal knockout models. Wnt3a/Loxl2 knockdown promotes ferroptosis in LCSCs and inhibits orthotopic tumor growth, with the strongest effect following dual-gene knockout. ZEB1 may be an important regulatory factor in this process.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 4","pages":"972-982"},"PeriodicalIF":4.3,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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