Journal for Immunotherapy of Cancer最新文献

{"title":"Hypoxia-induced RCOR2 promotes macrophage M2 polarization and CD8⁺ T-cell exhaustion by enhancing LIF transcription in hepatocellular carcinoma.","authors":"Wenbo Jia, Jinyi Wang, Weiming Yang, Zhijie Ding, Litao Liang, Chao Xu, Yanzhi Feng, Qingpeng Lv, Deming Zhu, Wenhu Zhao, Xiangyu Ling, Yong Yan, Xiaoming Ai, Yongping Zhou, Lianbao Kong, Wenzhou Ding","doi":"10.1136/jitc-2025-012314","DOIUrl":"10.1136/jitc-2025-012314","url":null,"abstract":"<p><strong>Background: </strong>The hypoxic microenvironment plays a crucial role in regulating the progression of hepatocellular carcinoma (HCC) and facilitating immune evasion. It is essential to gain a more comprehensive understanding of the pathways through which hypoxia influences HCC progression and immune evasion.</p><p><strong>Methods: </strong>We employed RNA sequencing, The Cancer Genome Atlas (TCGA) data analysis, clinical data analysis of HCC, and tissue microarray immunohistochemical analysis to identify key genes associated with hypoxia regulation and immune evasion. We investigated the biological functions of REST corepressor 2 (RCOR2) in tumor progression and immune evasion through mass cytometry, multiplex immunofluorescence, an orthotopic liver transplantation tumor model, in vitro co-culture systems, flow cytometry, and immunohistochemical analysis. Additionally, we used molecular techniques such as RNA sequencing, chromatin immunoprecipitation sequencing, and mass spectrometry to gain deeper insights into the potential molecular mechanisms underlying RCOR2.</p><p><strong>Results: </strong>We found that the hypoxia-related factor RCOR2 is upregulated in HCC and is associated with a poor prognosis. RCOR2 enhances the glycolytic process in HCC cells, thereby promoting the proliferation and metastasis of HCC cells under hypoxic conditions. Additionally, RCOR2 facilitates the M2 polarization of macrophages and contributes to the exhaustion of CD8⁺ T cells. Mechanistically, the hypoxic microenvironment increases the expression of RCOR2 through hypoxia-inducible factor 1-alpha. Concurrently, this microenvironment inhibits the ubiquitin-mediated degradation of RCOR2 by promoting its sumoylation, which facilitates its translocation to the nucleus. The sumoylation of RCOR2 further enhances the transcriptional activity of leukemia inhibitory factor (LIF). LIF, derived from HCC, contributes to the M2 polarization of macrophages, thereby facilitating immune evasion and playing a role in resistance to programmed cell death protein 1 (PD-1) therapies.</p><p><strong>Conclusions: </strong>Our research reveals that the RCOR2/LIF axis within the hypoxic microenvironment of HCC plays a significant role in immune evasion and identifies novel biomarkers associated with tumor resistance to anti-PD-1 therapy. This study provides potential therapeutic targets for HCC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>O</i>-GlcNAc transferase promotes immune evasion and immunotherapy resistance in uterine corpus endometrial cancer by targeting the glucocorticoid receptor.","authors":"Jingjing Wang, Yang Xie, Li Liu, Shuo Rong, Huanhuan Cai, Hao Zeng, Li Zhou, Keqiong Deng, Mengqiao Dai, Chao Xu, Ying Zhu, Zhibing Lu, Xuemin Song, Xiangtai Zeng, Shi Liu","doi":"10.1136/jitc-2025-011479","DOIUrl":"10.1136/jitc-2025-011479","url":null,"abstract":"<p><strong>Background: </strong>Although some tumors respond to immune checkpoint blockade therapy, checkpoint inhibitors have been unsuccessful in treating uterine corpus endometrial cancer (UCEC), and the underlying molecular mechanisms remain unclear.</p><p><strong>Methods: </strong>We investigated glucose flux regulation in UCEC cells with a focus on the hexosamine biosynthesis pathway (HBP). The role of <i>O</i>-linked <i>N</i>-acetylglucosamine (<i>O</i>-GlcNAc) transferase (OGT) and its interaction with the glucocorticoid receptor (GR) were examined using in vitro and in vivo models. A competitive peptide was designed to disrupt the interaction between OGT and GR.</p><p><strong>Results: </strong>We found that UCEC cells direct glucose flux to the HBP. OGT, a critical enzyme for protein <i>O</i>-GlcNAcylation, increased programmed death ligand-1 (PD-L1) expression while decreasing major histocompatibility complex class I (MHC-I) expression, thereby promoting immune evasion and resistance to immunotherapy. Mechanistically, OGT interacted with GR, leading to <i>O</i>-GlcNAcylation of GR at serine 132, which required prior phosphorylation of GR. Disruptions of the OGT-GR interaction with the competitive peptide reduced GR <i>O</i>-GlcNAcylation, decreased PD-L1 expression, and increased MHC-I expression. This, in turn, activated CD8⁺ T cell-mediated immunity against tumor cells in vitro and in vivo.</p><p><strong>Conclusions: </strong>Our findings reveal cross-talk between the HBP, steroid hormone pathway, and tumor immune evasion, and suggest potential strategies for sensitizing UCEC to immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preliminary qualification of a machine learning-based assessment of the tumor immune infiltrate as a predictor of outcome in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab.","authors":"Bernhard Scheiner, Pasquale Lombardi, Antonio D'Alessio, Gwangil Kim, Masoud Tafavvoghi, Oleksandr Petrenko, Robert D Goldin, Claudia A M Fulgenzi, Aria Torkpour, Lorenz Balcar, Francesco A Mauri, Katharina Pomej, Vera Himmelsbach, Maryam Barsch, Ciro Celsa, Giuseppe Cabibbo, Jaekyung Cheon, Anja Krall, Florian Hucke, Luca Di Tommaso, Monica Bernasconi, Lorenza Rimassa, Adel Samson, Bernardo Stefanini, Behrang Mozayani, Michael Trauner, Carolin Lackner, Rudolf Stauber, Francesco Vasuri, Fabio Piscaglia, Bertram Bengsch, Fabian Finkelmeier, Markus Peck-Radosavljevic, Lill-Tove Rasmussen Busund, Teresa Marafioti, Mohammad Rahbari, Mathias Heikenwalder, Matthias Pinter, Hong Jae Chon, Mehrdad Rakaee, David J Pinato","doi":"10.1136/jitc-2024-010975","DOIUrl":"10.1136/jitc-2024-010975","url":null,"abstract":"<p><p>Spontaneously immunogenic hepatocellular carcinoma (HCC), identified by a dense immune cell infiltrate (ICI), responds better to immunotherapy, although no validated biomarker exists to identify these cases. We used machine learning (ML) to quantify ICI from standard H&E-stained tissue and evaluated its correlation with characteristics of the tumor microenvironment (TME) and clinical outcome from atezolizumab plus bevacizumab (A+B).We therefore employed a supervised ML algorithm on 102 pretreatment H&E slides collected from patients treated with A+B. We quantified tumor, stroma and immune cell counts/mm² and dichotomized patients into ICI high and ICI low for clinicopathologic analysis. We correlated ICI signature with characteristics of the T-cell infiltrate (CD4+, FOXP3+, CD8+, PD1+) using multiplex immunohistochemistry in 62 resected specimens and evaluated gene expression profiles by bulk RNA sequencing in 44 samples.All patients treated with A+B were Child-Pugh A and received first-line A+B treatment for Barcelona Clinic Liver Cancer Stage C HCC (n=77, 75.5%) on a background of viral (n=53, 52%) and non-viral (n=49, 48%) liver disease. Median ICI density was 429.9 (IQR: 194.6-666.7) cells/mm² Two-thirds of patients (n=67, 65.7%) had ICI counts≥236/mm², derived as the optimal prognostic cut-off (ICI-high). Baseline characteristics, including disease etiology, liver function, performance status, stage, prior therapy and alpha-fetoprotein (AFP) levels, were comparable between ICI-high versus ICI-low patients. Patients with ICI-high demonstrated a significantly longer overall survival (OS) compared with ICI-low: 20.9 (95% CI: 13.8 to 27.9) versus 15.3 (95% CI: 6.0 to 24.6 months, p=0.026). Multivariable analyses demonstrated ICI-low status to remain as an independent prognostic parameter (adjusted HR (aHR): 2.02, 95% CI: 1.03 to 3.96) alongside AFP concentration (per 100 ng/mL: aHR 1.00, 95% CI: 1.00 to 1.00). ICI-high tumors were characterized by STC1 underexpression and enrichment in proinflammatory gene expression sets previously associated with response to immunotherapy. The proinflammatory environment identified by ICI status was not exclusively mediated by T-cell phenotype polarization as shown by a lack of correlation between ICI-high status and CD4+, CD4+FOXP3+, CD8+ and CD8+PD1+ T-cell density.In conclusion, we propose a ML-based algorithm to identify proinflamed HCC TMEs bearing a positive correlation with the patient's OS. Digital characterization of the TME should be validated as a tool to improve precision delivery of anticancer immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage NLRP3 activation and IL-1β release drive osimertinib-induced antitumor immunity.","authors":"Haiyang Yu, Xin Sun, Yan Li, Jing Pan, Xuemei Liu, Hongbin He, Haibo Wu, Yubei Sun, Yueyin Pan, Xiaojun Qian","doi":"10.1136/jitc-2025-012182","DOIUrl":"10.1136/jitc-2025-012182","url":null,"abstract":"<p><strong>Background: </strong>Despite the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC), patient outcomes vary even among those with identical EGFR mutations. This study investigates whether osimertinib, a third-generation EGFR-TKI, activates the nucleotide-binding oligomerization domain-like receptor protein-3 (NLRP3) inflammasome in macrophages to drive antitumor immunity and explores its mechanistic basis.</p><p><strong>Methods: </strong>Using bone marrow-derived macrophages from wild-type and gene-deficient mice, human peripheral blood mononuclear cells, and a Lewis lung cancer murine model, we assessed osimertinib-induced NLRP3 inflammasome activation, interleukin (IL)-1β secretion, pyroptosis, and tumor microenvironment (TME) remodeling. Mechanistic studies evaluated lysosomal dysfunction, calcium overload, mitochondrial damage, and reactive oxygen species (ROS) production. Clinical correlations were analyzed in patients with NSCLC treated with EGFR-TKIs.</p><p><strong>Results: </strong>Osimertinib triggered NLRP3 inflammasome activation in macrophages via lysosomal dysfunction-induced calcium overload, leading to mitochondrial damage and ROS production, which acted as damage-associated molecular patterns to activate NLRP3. This process promoted IL-1β release, pyroptosis, and CD8⁺ T-cell activation while suppressing regulatory T cells in the TME. In murine models, osimertinib's antitumor effects were abrogated by NLRP3 inhibition (MCC950) and enhanced by recombinant IL-1β (rIL-1β) co-administration (p<0.01). Clinically, high NLRP3 and IL-1β expression in tumor-associated macrophages (TAMs) correlated with prolonged progression-free survival (p<0.01) and overall survival (p<0.01) in EGFR-TKI-treated patients with NSCLC.</p><p><strong>Conclusions: </strong>Osimertinib exerts off-target immunomodulatory effects by activating the tumor-extrinsic NLRP3 inflammasome, linking mitochondrial-lysosomal crosstalk to antitumor immunity. NLRP3 and IL-1β in TAMs emerge as predictive biomarkers for EGFR-TKI efficacy, while rIL-1β combination therapy represents a novel strategy to enhance clinical outcomes.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abscopal effects in patients with malignant melanoma treated with radiotherapy and immune checkpoint inhibition: analysis of a large observational multicenter study.","authors":"Simone Ferdinandus, Alexander Rühle, Allison Lamrani, Charlotte Frei, Justus Kaufmann, Matthias Mäurer, Georg Wurschi, Ping Jiang, Felix Ehret, Andrea Baehr, Annika Hardt, Raphael Bodensohn, Lukas Käsmann, Maria Waltenberger, Davide Scafa, Julian P Layer, Esther G C Troost, Sally A Elkhamisy, Danny Jazmati, Cindy Franklin, Sebastian Neppl, Anna Hagemeier, Maike Trommer","doi":"10.1136/jitc-2025-012717","DOIUrl":"10.1136/jitc-2025-012717","url":null,"abstract":"<p><strong>Background: </strong>Abscopal effect (AbE), the regression of non-irradiated metastatic lesions (NILs) following radiotherapy (RT), is relevant in patients with malignant melanoma (MM) with progressive disease (PD) under immune checkpoint inhibition (ICI) as resistance to immunotherapy. In the \"ARTIC\" trial, we assessed the incidence of AbE in patients with progressive MM by evaluating the effect of RT on NILs.</p><p><strong>Methods: </strong>ARTIC (<u>A</u>bscopal effects in metastasized cancer patients treated with <u>R</u>adio<u>T</u>herapy and <u>I</u>mmune <u>C</u>heckpoint inhibition) (ARO (Arbeitsgemeinschaft Radiologische Onkologie) 2022-10, DRKS00032390) retrospectively screened clinical records of patients with stage IV MM with PD under ICI. Patients received RT for metastases and had ≥1 NIL outside the RT field (=control lesion). NILs were evaluated according to iRECIST (immune Response Evaluation Criteria in Solid Tumors): abscopal response (AR): size reduction ≥30%, abscopal progression (AP): size increase ≥20%, abscopal control (AC): all others. Patients with AR and/or AC were categorized as abscopal benefit (AB), patients with AP and/or mixed response=no AB. RT details and factors influencing AR were analyzed.</p><p><strong>Results: </strong>After screening clinical records of 3773 patients with stage IV tumor from 12 oncological centers in Germany, we identified 47 patients with MM with 115 NILs. RT targeted metastases in brain (38.3%) and lung (19.1%), primarily using stereotactic RT (29.8%). The mean time interval between the end of ICI and RT was 3.53±5.67 months. AR was achieved in 19.1% of patients and 29.1% of lesions. Compared with stereotactic RT, normofractionated or other (non-stereotactic) RT regimens significantly reduced the probability of AB (OR=0.092, p=0.04, 95% CI: (0.007 to 0.758)). Longer ICI-to-RT intervals were associated with reduced mortality risk (HR=0.703, p=0.007, 95% CI: (0.544 to 0.908)). Patients with AB had a longer median overall (17 vs 9 months) and a longer median progression-free survival (4 vs 2 months).</p><p><strong>Conclusions: </strong>RT can induce AR in patients with MM with PD under ICI, particularly with hypofractionated regimens and long ICI-to-RT intervals. Our findings can serve as a reference for designing prospective trials.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12496099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T cell subsets of urine-derived lymphocytes (UDLs) serve as an indicator of TILs and reflect immunological sex differences in bladder cancer.","authors":"Johanna M Schafer, No-Joon Song, Tong Xiao, Timothy D Gauntner, Kyeong Joo Jung, Emily G Fitts, Krishan Kumar, Hyeong Seon Jeon, Ryan A Elaoud, Kelsi Reynolds, Vincent M Caruso, Trevor G Levin, David McConkey, Cheryl T Lee, Kamal S Pohar, Steven K Clinton, William Carson, Dongjun Chung, Zihai Li, Debasish Sundi","doi":"10.1136/jitc-2025-012050","DOIUrl":"10.1136/jitc-2025-012050","url":null,"abstract":"<p><strong>Background: </strong>Bladder cancer is unique among visceral malignancies in that urine, which can be easily obtained, has prolonged contact with bladder tumors. Urinary biomarkers offer the potential to provide insight into the host and tumor immune microenvironment to guide therapeutic strategies. We evaluated the immune cellular composition of urine (urine-derived lymphocytes (UDLs)) versus tumor (tumor-infiltrating lymphocytes (TILs)).</p><p><strong>Methods: </strong>We employed high-dimensional flow cytometry analyses on immune cells from tumors (TILs), urine (UDLs), and peripheral blood (peripheral blood mononuclear cells) among patients with bladder cancer. We performed multiplexed immunofluorescence (mIF) of matched tumors to provide spatial context to our findings, comparing deep/invasive and superficial/urine-facing regions of matched tumors.</p><p><strong>Results: </strong>Our findings suggest that the CD4⁺ and CD8⁺ T cell subsets of UDLs characterized by flow cytometry had similar phenotypic profiles to those found in TILs (cell clusters quantified by multidimensional scaling and differentiation states). Results of mIF imaging with a panel of phenotypic and functional T cell markers suggested that UDLs reflected TILs in both superficial and deep tumor sections. We also found sex-dependent patterns in TILs and UDLs, indicating the male bladder cancer tumor microenvironment is enriched in exhausted CD4⁺ and CD8⁺ T cells, while the female bladder cancer microenvironment is enriched for activated T cells.</p><p><strong>Conclusions: </strong>Assessment of UDLs opens avenues of non-invasive biomarker development in clinical settings where bladder cancer TILs are hypothesized to predict clinical response. UDLs may also reflect sex-based differences in antitumor immunity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12496083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting immunosuppressive macrophages by CSRP2-regulated CCL28 signaling sensitizes hepatocellular carcinoma to lenvatinib.","authors":"Changzhou Chen, Sheng Su, Pengcheng Wang, Xinming Ye, Songyang Yu, Yu Gong, Zehuan Li, Jia Li, Zhiqiang Hu, Xiaowu Huang","doi":"10.1136/jitc-2025-012201","DOIUrl":"10.1136/jitc-2025-012201","url":null,"abstract":"<p><strong>Background: </strong>Despite comparable survival benefit has been obtained, the drug resistance remarkably reduced lenvatinib clinical efficacy. Here, we aimed to identify the potential mechanism by which cysteine and glycine-rich protein 2 (CSRP2) regulates the development of hepatocellular carcinoma (HCC) and participates in the resistance to lenvatinib.</p><p><strong>Methods: </strong>We harnessed RNA sequencing, multiplex immunofluorescence staining, and hydrodynamic tail vein (HTV) injection HCC model to systematically explore the function of CSRP2 in HCC progression. To precisely delineate how immunosuppressive macrophages, influenced by CSRP2-regulated C-C motif chemokine ligand 28 (CCL28) signaling, respond to lenvatinib-induced cytotoxicity, we established an in vitro co-culture system and conducted functional cytotoxicity assays.</p><p><strong>Results: </strong>Using RNA sequencing, multiplex immunofluorescence staining and HTV injection HCC mouse model, we identified CSRP2 as one of the most significantly upregulated genes in HCC tissues. CSRP2 overexpression drives anti-lenvatinib resistance by inducing high levels of tumor-associated macrophages (TAMs) infiltration and reshaping an immunosuppressive microenvironment. Then flow cytometry, mass spectrometry and chromatin immunoprecipitation were conducted to clarify the underlying mechanism of CSRP2. We showed CSRP2 promotes phosphorylation of activating transcription factor 2 (ATF2) at Thr69/71, leading to the transcriptional activation of CCL28 expression. HCC-derived CCL28 recruits TAMs to drive immunosuppression and anti-lenvatinib tolerance. BI6901, a potent and selective CCR10 antagonist, blocked TAMs recruitment and enhanced T-cell activation. Combining CCR10 inhibition improved the therapeutic benefit of anti-lenvatinib in HCC.</p><p><strong>Conclusions: </strong>These results illustrate that CSRP2 regulates the tumor microenvironment to promote HCC growth and drive lenvatinib tolerance via the CSRP2/ATF2/CCL28 axis. Targeting this pathway could synergize with lenvatinib to treat HCC more effectively.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12496042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial transcriptomic profiling of metastatic renal cell carcinoma identifies chemokine-driven macrophage and CD8+ T-cell interactions predictive of immunotherapy response.","authors":"Charis Kalogirou, Markus Krebs, Andreas S Kunz, Oliver Hahn, Hubert Kübler, Marcel Schwinger, Arndt Hartmann, Astrid Schmieder, Markus Eckstein","doi":"10.1136/jitc-2025-012991","DOIUrl":"10.1136/jitc-2025-012991","url":null,"abstract":"<p><strong>Background: </strong>Metastatic renal cell carcinoma (mRCC) still lacks tissue-based biomarkers that predict benefit from first-line immune checkpoint inhibitor (ICI) regimens. High-resolution spatial transcriptomics can dissect the tumor microenvironment (TME) and reveal prognostic niches invisible to bulk assays, offering a path toward precision immunotherapy.</p><p><strong>Methods: </strong>Formalin-fixed, paraffin-embedded samples from 12 therapy-naïve patients with mRCC treated with ICI-based combinations were profiled with 10x Genomics Visium and NanoString COSMx. Six patients contributed matched metastatic lesions. Cell-type deconvolution used robust cell type decomposition with a public single-cell RNA-seq reference. Clinical outcomes (mean follow-up 16.75 months) were correlated with spatial features. Validation employed Phase 2/3 JAVELIN Renal 101 as well as Checkmate 010/025 transcriptomic data.</p><p><strong>Results: </strong>Spatial transcriptomics uncovered pronounced divergences between primary tumors and metastases in cellular composition and microarchitectural organization. Canonical RCC molecular subtypes displayed marked intrapatient and interpatient spatial heterogeneity, underscoring limitations of bulk classifications. Five recurrent immune niches emerged across samples. One niche-rich in macrophages and CD8⁺ T cells and defined by chemokine signaling-was closely associated with objective response in metastatic lesions yet absent or infrequent in matched primaries. A gene signature reflecting this niche stratified responders within the immuno-oncology (IO) -treated arms of JAVELIN 101 and CheckMate 010/025 trials. On the other hand, signatures derived from angiogenic tumor cell-rich niches defined responders within the comparator arms (tyrosine kinase inhibitor/everolimus) in these trials.</p><p><strong>Conclusion: </strong>Metastasis-specific immune niches, rather than primary-tumor characteristics, appear decisive for ICI efficacy in mRCC. Spatial transcriptomic profiling can identify these clinically relevant microenvironments and generate transferable gene signatures, supporting biomarker-driven patient selection and trial design. Integrating spatial TME analysis into future studies may accelerate personalized immunotherapy strategies for mRCC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12496100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transformer-based AI approach to unravel long-term, time-dependent prognostic complexity in patients with advanced NSCLC and PD-L1 ≥50%: insights from the pembrolizumab 5-year global registry.","authors":"Alessio Cortellini, Valentina Santo, Leonardo Brunetti, Edoardo Garbo, David J Pinato, Giulia La Cava, Jarushka Naidoo, Artur Katz, Monica Loza, Joel W Neal, Carlo Genova, Scott Gettinger, So Yeon Kim, Ritujith Jayakrishnan, Talal El Zarif, Marco Russano, Federica Pecci, Alessandro Di Federico, Joao V Alessi, Michele Montrone, Dwight H Owen, Sara Ramella, Diego Signorelli, Mary Jo Fidler, Mingjia Li, Andrea Camerini, Balazs Halmos, Bruno Vincenzi, Giulio Metro, Francesco Passiglia, Sai Yendamuri, Annalisa Guida, Michele Ghidini, Antonio D'Alessio, Giuseppe L Banna, Claudia A M Fulgenzi, Salvatore Grisanti, Francesco Grossi, Armida D'Incecco, Eleni Josephides, Mieke Van Hemelrijck, Alessandro Russo, Alain Gelibter, Gianpaolo Spinelli, Monica Verrico, Bartłomiej Tomasik, Raffaele Giusti, Kirsty Balachandran, Emilio Bria, Martin Sebastian, Maximilian Rost, Martin Forster, Uma Mukherjee, Lorenza Landi, Francesca Mazzoni, Avinash Aujayeb, Manuel Dupont, Alessandra Curioni-Fontecedro, Rita Chiari, Vincenzo Sforza, Marcello Tiseo, Alex Friedlaender, Alfredo Addeo, Federica Zoratto, Michele De Tursi, Luca Cantini, Elisa Roca, Giannis Mountzios, Danilo Rocco, Luigi Della Gravara, Sukumar Kalvapudi, Alessandro Inno, Paolo Bironzo, Rafael Di Marco Barros, David O'Reilly, Orla Fitzpatrick, Eleni Karapanagiotou, Isabelle Monnet, Javier Baena, Marianna Macerelli, Aida Piedra, Francesco Agustoni, Diego Luigi Cortinovis, Giuseppe Tonini, Gabriele Minuti, Chiara Bennati, Laura Mezquita, Teresa Gorría, Alberto Servetto, Teresa Beninato, Giuseppe Lo Russo, Arsela Prelaj, Andrea De Giglio, Jacobo Rogado, Laura Moliner, Ernest Nadal, Federica Biello, Frank Aboubakar Nana, Anne-Marie Dingemans, Joachim G J V Aerts, Roberto Ferrara, Taher Abu Hejleh, Kazuki Takada, Abdul Rafeh Naqash, Marina Chiara Garassino, Solange Peters, Heather A Wakelee, Amin H Nassar, Biagio Ricciuti, Paolo Soda, Camillo Maria Caruso, Valerio Guarrasi","doi":"10.1136/jitc-2025-012423","DOIUrl":"10.1136/jitc-2025-012423","url":null,"abstract":"<p><strong>Background: </strong>With nearly one-third of patients with advanced non-small cell lung cancer (NSCLC) and PD-L1 Tumor Proportion Score≥50% surviving beyond 5 years following first-line pembrolizumab, long-term outcomes challenge traditional paradigms of cancer prognostication. The emergence of non-cancer-related factors and time-dependent trends underscores the need for advanced analytical frameworks to unravel their complex interplay.</p><p><strong>Methods: </strong>We analyzed the Pembro-real 5Y registry, a global real-world dataset of 1050 patients treated across 61 institutions in 14 countries with a long-term follow-up and a large panel of baseline variables. Two complementary approaches were employed: ridge regression, chosen for its ability to address multicollinearity while retaining interpretability, and not another imputation method (NAIM), a transformer-based artificial intelligence model designed to handle missing data without imputation. Endpoints included risk of death at 6, 12, 24, 60 months and 5-year survival.</p><p><strong>Results: </strong>The ridge regression model achieved a c-statistic of 0.66 (95% CI: 0.59 to 0.72) for the risk of death and an area under the curve (AUC) of 0.72 (95% CI: 0.65 to 0.78) for 5-year survival, identifying Eastern Cooperative Oncology Group Performance Status (ECOG-PS)≥2, increasing age, and metastatic burden as primary risk factors. However, wide CIs for some predictors highlighted statistical instability. NAIM demonstrated robust handling of missing data, with a c-index of 62.98±2.11 for risk of death and an AUC of 60.52±3.71 for 5-year survival. The comprehensive SHapley Additive exPlanations analysis revealed dynamic, time-dependent patterns, with early mortality dominated by acute factors (eg, ECOG-PS, steroids) and long-term outcomes increasingly influenced by systemic health markers (eg, absence of hypertension, increasing body mass index). Unexpected insights included the protective role of dyslipidemia (but not statins) and the nuanced impact of smoking status, reflecting evolving disease dynamics and host-tumor interplay.</p><p><strong>Conclusions: </strong>Our integrative framework illuminates the complexity of long-term outcomes in patients with NSCLC treated with pembrolizumab, uncovering dynamic, non-linear prognostication trends. This analysis provides insights into patient trajectories, emphasizing the need for holistic, long-term management strategies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic modulation of claudin18.2 expression and remodeling of the tumor microenvironment in gastric cancer during chemo-immunotherapy.","authors":"Sung Hee Lim, Takeshi Kuwata, Minae An, Jung Yong Hong, Seung Tae Kim, Yuki Matsubara, Kohei Shitara, Jeeyun Lee","doi":"10.1136/jitc-2025-012683","DOIUrl":"10.1136/jitc-2025-012683","url":null,"abstract":"<p><strong>Background: </strong>Claudin 18.2 (CLDN18.2) is a tight junction protein retained in malignant transformation of gastric cancer (GC) and is a promising therapeutic target. Despite the clinical benefit of zolbetuximab in CLDN18.2-positive tumors, the dynamic expression of CLDN18.2 during chemoimmunotherapy and its implications in the tumor microenvironment (TME) remain poorly understood.</p><p><strong>Methods: </strong>In a prospective single-arm phase II trial, we evaluated serial tumor biopsies from patients with advanced GC receiving first-line chemotherapy (capecitabine/oxaliplatin) with sequential pembrolizumab. CLDN18.2 expression was assessed by immunohistochemistry, and integrated molecular analyses-including whole transcriptome, whole exome, and single-cell RNA sequencing-were performed to explore TME alterations and molecular correlates.</p><p><strong>Results: </strong>Among 57 patients, 40.4% were CLDN18.2-positive at baseline. CLDN18.2 positivity was associated with diffuse-type histology, higher programmed death-ligand 1 (PD-L1) combined positive scores, and an immune-inflamed, stroma-rich TME characterized by enhanced T cell infiltration, transforming growth factor-β signaling, and matrix remodeling. Gene set enrichment analyses revealed immune activation and stromal remodeling in CLDN18.2-positive tumors. Single-cell analysis showed increased regulatory T cells and galectin-3-CD44 signaling in CLDN18.2-positive tumors. After one cycle of chemotherapy, CLDN18.2 expression was lost in 40% of initially positive tumors, while 10% of initially negative tumors gained expression-particularly in fibrotic TMEs. Survival outcomes were not significantly different between CLDN18.2-positive and CLDN18.2-negative groups; however, patients negative for both CLDN18.2 and PD-L1 showed poorer prognosis.</p><p><strong>Conclusions: </strong>CLDN18.2 expression is dynamically regulated during chemoimmunotherapy and is associated with a distinct immunosuppressive and fibrotic TME. These findings highlight the importance of repeated biomarker assessment and suggest potential combinatorial therapeutic strategies targeting both epithelial and stromal compartments in GC.</p><p><strong>Trial registration number: </strong>NCT04249739.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}