記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neoantigens are crucial for antitumor immunity and immune checkpoint inhibitor (ICI) efficacy by triggering strong immune responses. However, conventional methods for identifying neoantigens, such as whole-exon sequencing and short-read RNA sequencing (RNA-seq), appear to be insufficient, and the tumor mutational burden cannot sufficiently predict ICI efficacy. In this study, we employed a proteogenomic approach using long-read RNA-seq with Pacific Biosciences Single-Molecule Real-Time Sequencing technology to analyze full-length transcripts in combination with the human leukocyte antigen ligandome. As a result, many neoantigen candidates were identified, which were unregistered in a comprehensive database, including those from non-coding regions. Additionally, we validated the responses of specific T cell receptors (TCRs) to these candidates and identified several pairs of TCRs and neoantigens. These findings highlight the presence of more diverse neoantigens than expected that cannot be identified by conventional methods.

DOI： 10.1016/j.celrep.2025.116781

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Despite advancements in diagnostic and therapeutic strategies, lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality due to its aggressive metastatic potential. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme that regulates oxidative stress and is regarded as a tumor suppressor. However, studies have demonstrated that SOD3 can either promote or inhibit cell proliferation and survival in various cancers, and its molecular mechanisms within the tumor microenvironment are poorly understood. In this study, we report a breakthrough in uncovering the role of SOD3 derived from cancer-associated fibroblasts (CAFs) in LUAD. Using LUAD xenograft models co-implanted with SOD3-overexpressing CAFs (CAFSOD3), we observe an aggressive tumor phenotype characterized by increased lymphangiogenesis and lymphatic vessel invasion (LVI) of the tumor. Additionally, LUAD patients with elevated SOD3 levels exhibit a higher incidence of LVI and metastasis. Notably, RNA sequencing of CAFSOD3 reveals that SOD3-mediated VEGF-dependent tumor progression and lymphangiogenesis are up-regulated. Furthermore, single-cell transcriptomic analysis of LUAD clinical samples confirms a strong correlation between SOD3 expression in fibroblasts and characteristics of tumor exacerbation, such as lymphangiogenesis and metastasis. These findings underscore new insights into the role of CAF-derived SOD3 in LUAD progression and highlight its potential as a biomarker and therapeutic target.

DOI： 10.1007/s10456-025-10005-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cancer-associated fibroblasts (CAF) play immunosuppressive roles in the tumor microenvironment. Specifically, they reportedly act as physical barriers preventing immune cell infiltration. However, the spatial relationships between CAFs and cancer cells in antitumor immunity remain unknown. In this study, we established three-dimensional (3D) constructs, in which the spatial relationships were controlled using a 3D bioprinter. Using these models, we found that the mixed distribution of fibroblasts (FB) and cancer cells suppressed the antitumor immunity more than the surrounding distribution of FBs as physical barriers. The 3D construct with mixed distribution promoted TGFβ and periostin (encoded by Postn gene) cross-talk, resulting in immunosuppression. Postn knockdown in FBs decreased the TGFβ production in the mixed 3D construct and activated antitumor immunity both in vitro and in vivo. Clinically, patients with head and neck cancer or lung cancer showing a mixed distribution of α-smooth muscle actin+ myofibroblast-like CAFs exhibited worse prognosis after PD-1 blockade therapies, and lower CD8+ T-cell infiltration than those that had CAFs surrounding cancer cells. Overall, our findings suggest that the close interactions of CAFs and cancer cells facilitate immunosuppression, rather than the physical barriers created by CAFs, highlighting their potential as biomarkers and therapeutic targets for cancer immunotherapies based on spatial relationships. Furthermore, this study highlights the beneficial applications of 3D bioprinters.

DOI： 10.1158/2326-6066.CIR-24-1144

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.

DOI： 10.1371/journal.pone.0300644

PubMed

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記述言語：英語  

DOI： 10.1007/s00109-023-02384-7

Web of Science

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開催年月日： 2025年6月28日 - 2025年6月30日

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2024年4月

記述言語：日本語  

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開催年月日： 2023年4月

記述言語：日本語  

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開催年月日： 2022年11月

記述言語：日本語  

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記述言語：英語   会議種別：口頭発表（一般）  

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