記述言語：英語   掲載種別：研究論文（学術雑誌）  

Immune checkpoint blockade has transformed melanoma therapy but is frequently limited by acquired resistance. Focal adhesion kinase (FAK) and its homolog PYK2 are nonreceptor tyrosine kinases that coordinate cell-matrix adhesion and cytoskeletal signaling. In this study, we define the distinct roles of FAK (as the principal scaffold) and PYK2 (in a supportive capacity) in IFN-γ-mediated immune checkpoint blockade resistance. Label-free phosphoproteomic profiling revealed that IFN-γ stimulation drives extensive phosphorylation across pathways governing cytoskeletal remodeling, transcriptional regulation, mRNA splicing, and ribosomal RNA biogenesis. Selective FAK inhibition markedly suppressed IFN-γ-induced signal transducer and activator of transcription 1 and PD-L1 upregulation, and the addition of PYK2 blockade achieved maximal suppression, culminating in enhanced CD8+ T-cell-mediated tumor cytotoxicity. In an anti-PD-1-resistant murine melanoma model, high tumoral FAK expression correlated with treatment failure. Analysis of The Cancer Genome Atlas-Skin Cutaneous Melanoma cohort showed that FAK levels associate with immunosuppressive gene signatures, whereas in an independent clinical dataset (GSE91061), patients exhibiting post-treatment downregulation of FAK experienced improved outcomes. Single-cell RNA sequencing distinguished tumor cell-intrinsic FAK expression from PYK2 enrichment in immune subsets. Together, these data position FAK as the dominant driver of IFN-γ-dependent resistance, with PYK2 playing a subsidiary role, and suggest that selective FAK targeting-potentially combined with limited PYK2 inhibition-may overcome immune checkpoint blockade resistance in melanoma.

DOI： 10.1016/j.jid.2025.09.376

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study investigated the regulation of PD-L1 expression by calcium signaling in oral squamous cell carcinoma (OSCC). We found that IFN-γ stimulation markedly altered the intracellular proteome and activated calcium-associated pathways. Pharmacological inhibition of store-operated calcium entry (SOCE) using the Orai1 inhibitor Synta66 suppressed IFN-γ-induced PD-L1 expression in a dose-dependent manner. Consistently, knockdown of Orai1 or STIM1 attenuated PD-L1 induction under IFN-γ stimulation, while basal expression remained unchanged. Inhibition of CaMK2 and CaMKK2 also reduced PD-L1 expression, indicating involvement of calmodulin-dependent kinase pathways. Functionally, Orai1 or STIM1 knockdown enhanced CD8⁺ T cell-mediated suppression of OSCC cell proliferation. Collectively, these results demonstrate that SOCE-mediated calcium signaling and downstream kinases regulate IFN-γ-induced PD-L1 expression and suggest that targeting SOCE components could represent a novel therapeutic approach to overcoming tumor immune evasion in OSCC. (132 words).

DOI： 10.1016/j.jphyss.2026.100063

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Triple-negative breast cancer (TNBC), which lacks expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is associated with poor prognosis. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic option for TNBC, but their efficacy remains limited due to resistance. In this study, we investigated whether the non-receptor tyrosine kinase Src (Src tyrosine kinase) regulates interferon-gamma (IFNγ)-induced expression of programmed death-ligand 1 (PD-L1). IFNγ stimulation of TNBC and luminal A breast cancer cell lines induced time-dependent phosphorylation of Src at its activation site (Y419). Pharmacological inhibition of Src significantly suppressed IFNγ-induced PD-L1 mRNA and protein expression, as well as activation of PD-L1-related transcription factors, suggesting transcriptional regulation. In co-culture assays with CD8+ T-cells, TNBC cells were more susceptible to T-cell-mediated cytotoxicity compared with luminal A cells, and Src inhibition further enhanced this cytotoxicity. These findings indicate that Src plays a crucial role in IFNγ-mediated PD-L1 expression and immune evasion in TNBC cell lines. Src inhibition may represent a promising combinatorial strategy to enhance antitumor immunity in TNBC cell lines.

DOI： 10.1016/j.jphs.2025.12.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Lymph node metastasis, primarily caused by the migration of oral squamous cell carcinoma (OSCC) cells, stands as a crucial prognostic marker. We have previously demonstrated that EP4, a subtype of the prostaglandin E2 (PGE2) receptor, orchestrates OSCC cell migration via Ca2+ signaling. The exact mechanisms by which EP4 influences cell migration through Ca2+ signaling, however, is unclear. Our study aims to clarify how EP4 controls OSCC cell migration through this pathway. We find that activating EP4 with an agonist (ONO-AE1-473) increased intracellular Ca2+ levels and the migration of human oral cancer cells (HSC-3), but not human gingival fibroblasts (HGnF). Further RNA sequencing linked EP4 to calmodulin-like protein 6 (CALML6), whose role remains undefined in OSCC. Through protein-protein interaction network analysis, a strong connection is identified between CALML6 and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), with EP4 activation also boosting mitochondrial function. Overexpressing EP4 in HSC-3 cells increases experimental lung metastasis in mice, whereas inhibiting CaMKK2 with STO-609 markedly lowers these metastases. This positions CaMKK2 as a potential new target for treating OSCC metastasis. Our findings highlight CALML6 as a pivotal regulator in EP4-driven mitochondrial respiration, affecting cell migration and metastasis via the CaMKK2 pathway.

DOI： 10.1038/s42003-024-06231-4

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(一社)日本臨床免疫学会  

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