Journal for Immunotherapy of Cancer最新文献

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Commentary on "Targeted release of a bispecific fusion protein SIRPα/Siglec-10 by oncolytic adenovirus reinvigorates tumor-associated macrophages to improve therapeutic outcomes in solid tumors". “溶瘤腺病毒靶向释放双特异性融合蛋白SIRPα/ siglece -10,使肿瘤相关巨噬细胞恢复活力,改善实体瘤的治疗效果”。
IF 10.3 1区 医学
Journal for Immunotherapy of Cancer Pub Date : 2025-06-15 DOI: 10.1136/jitc-2025-012218
Marc Lecoultre, Aya El Helali
{"title":"Commentary on \"Targeted release of a bispecific fusion protein SIRPα/Siglec-10 by oncolytic adenovirus reinvigorates tumor-associated macrophages to improve therapeutic outcomes in solid tumors\".","authors":"Marc Lecoultre, Aya El Helali","doi":"10.1136/jitc-2025-012218","DOIUrl":"https://doi.org/10.1136/jitc-2025-012218","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs), long exploited by cancers to evade immune detection, can now be reprogrammed into potent antitumor effectors through cutting-edge viral engineering. In a landmark study published in the <i>Journal for Immunotherapy of Cancer</i>, Zhang <i>et al</i> introduced an innovative adenovirus, Adv-mSS, that blocks two critical \"don't eat me\" signals, CD47 and CD24, used by tumors to paralyze macrophage activity. By converting immunosuppressive TAMs into tumor-engulfing predators and reigniting CD8 T-cell response, Adv-mSS eradicated tumors across multiple preclinical models. This strategy offers a promising avenue for activating both innate and adaptive immunity against cancer and may address key limitations of current immunotherapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multiomics identifies tumor-intrinsic SREBP1 driving immune exclusion in hepatocellular carcinoma. 多组学鉴定肝癌中肿瘤固有的SREBP1驱动免疫排斥。
IF 10.3 1区 医学
Journal for Immunotherapy of Cancer Pub Date : 2025-06-15 DOI: 10.1136/jitc-2025-011537
Rebekah E Dadey, Ruxuan Li, Jake Griner, Jie Chen, Arjun Singh, Brian Isett, Sarah Newman, Ryan Augustin, Aofei Li, Joseph A Manning, Satdarshan P Monga, Aatur Singhi, David A A Geller, Carsten Krieg, Ioannis K Zervantonakis, Jason John Luke, Riyue Bao
{"title":"Multiomics identifies tumor-intrinsic SREBP1 driving immune exclusion in hepatocellular carcinoma.","authors":"Rebekah E Dadey, Ruxuan Li, Jake Griner, Jie Chen, Arjun Singh, Brian Isett, Sarah Newman, Ryan Augustin, Aofei Li, Joseph A Manning, Satdarshan P Monga, Aatur Singhi, David A A Geller, Carsten Krieg, Ioannis K Zervantonakis, Jason John Luke, Riyue Bao","doi":"10.1136/jitc-2025-011537","DOIUrl":"https://doi.org/10.1136/jitc-2025-011537","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) have improved patient outcomes in hepatocellular carcinoma (HCC); however, most patients do not experience durable benefit. The non-T cell-inflamed tumor microenvironment, characterized by limited CD8<sup>+</sup> T-cell infiltration, reduced dendritic cell function, and low interferon-γ-associated gene expression, is associated with a lower likelihood of response to ICI. To nominate new therapeutic targets for overcoming ICI resistance in HCC, we conducted a large-scale multiomic analysis on 900+human specimens (RNA sequencing (RNA-seq), proteomics) and 31 tumor single-cell (sc) RNA-seq samples, with tissue validation through imaging mass cytometry (IMC) and spatial lipidomics by matrix-assisted laser desorption/ionization (MALDI), with experimental investigation by in vitro CD8<sup>+</sup> T-cell recruitment and macrophage polarization functional assays using three-dimensional (3D) co-culture models. We discovered 32 oncogenic pathways associated with immune exclusion, with sterol regulatory element binding protein 1 (SREBP1, encoded by <i>SREBF1</i>) as a hub regulator. scRNA-seq analysis showed that SREBP1 signaling is associated with enriched lipid biogenesis pathways in tumor cells, elevated immunosuppressive markers in macrophages, and diminished CD8<sup>+</sup> T-cell infiltration. Integration of IMC and MALDI images revealed distinct lipid species differentially abundant in tumor regions with low versus high CD8<sup>+</sup> T cell infiltration. Functional studies in a 3D in vitro tumor-immune co-culture system demonstrated that CRISPR-mediated <i>SREBF1</i> knockout (KO) in HepG2 cells reduced monocyte recruitment, decreased expression of the protumorigenic CD206 marker in macrophages, and enhanced CD8<sup>+</sup> T-cell migration compared with wild-type (WT) (p<0.0001). RNA-seq of <i>SREBF1</i> KO versus WT tumor cells confirmed suppression of lipid biosynthesis genes.Our findings nominate an atlas of tumor-intrinsic drivers of immune exclusion, particularly SREBP1 via pro-tumorigenic macrophage (M2-like) reprogramming. These pathways may represent novel therapeutic targets to enhance antitumor immunity and deserve further study as targeted therapy candidates to enhance ICI in HCC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibiting CMTM4 reverses the immunosuppressive function of myeloid-derived suppressor cells and augments immunotherapy response in cervical cancer. 抑制CMTM4逆转髓源性抑制细胞的免疫抑制功能,增强宫颈癌的免疫治疗反应。
IF 10.3 1区 医学
Journal for Immunotherapy of Cancer Pub Date : 2025-06-13 DOI: 10.1136/jitc-2025-011776
Jianyi Ding, Haoran Hu, Yashi Zhu, Xinxin Xu, Bo Yin, Meiqin Yang, Huijuan Zhou, Tiefeng Huang, Mengjie Li, Yifan Kou, Zilale Rahim, Baoyou Huang, Ang Li, Wei Wang, Lingfei Han
{"title":"Inhibiting CMTM4 reverses the immunosuppressive function of myeloid-derived suppressor cells and augments immunotherapy response in cervical cancer.","authors":"Jianyi Ding, Haoran Hu, Yashi Zhu, Xinxin Xu, Bo Yin, Meiqin Yang, Huijuan Zhou, Tiefeng Huang, Mengjie Li, Yifan Kou, Zilale Rahim, Baoyou Huang, Ang Li, Wei Wang, Lingfei Han","doi":"10.1136/jitc-2025-011776","DOIUrl":"10.1136/jitc-2025-011776","url":null,"abstract":"<p><p>CKLF (chemokine-like factor)-like MARVEL transmembrane domain-containing family member 4 (CMTM4), belonging to the CMTM family of transmembrane domain proteins, plays a significant role in the initiation, progression, and metastasis of cancer. Nevertheless, its involvement in tumor immunity remains elusive. In the present investigation, we observed an upregulation of CMTM4 expression in patients with cervical cancer (CC), which also serves as a prognostic indicator for patients with CC. In vitro experiments and therapeutic models have demonstrated that CMTM4 upregulates the expansion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment via the CCL2 (C-C motif chemokine ligand 2)/CCR2 (C-C motif chemokine ligand 2) and IL-6 (interleukin-6)/GP130 (glycoprotein 130) axes. This process exerts immunosuppressive effects and promotes the occurrence and progression of CC. Mechanistically, CMTM4 interacts and stabilizes PHB2 (prohibitin 2) through post-translational modification, which further induces activation of the STING (stimulator of interferon genes)/TBK1 (TANK-binding kinase 1)/STAT6 (signal transducer and activator of transcription 6) pathway, facilitating the nuclear translocation of STAT6 which binds to the CCL2/IL-6 promoter, leading to the upregulation of CCL2/IL-6 transcription expression. Importantly, targeting CMTM4 with CMTM4-small interfering RNA enhanced the effectiveness of anti-programmed cell death protein 1 (anti-PD-1) therapy. Our study identifies CMTM4 as a crucial determinant guiding the homing of MDSCs to CC, thereby contributing to MDSCs-mediated immune suppression and tumor progression. The combination of CMTM4 inhibition and anti-PD-1 treatment shows promising antitumor efficacy against CC. These findings offer novel insights into the tumor microenvironment and have the potential to inform the development of innovative immunotherapy approaches for CC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293768","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}
引用次数: 0
EZH2 inhibition and 5-azacytidine enhance antitumor immunity in PTEN-deficient glioblastoma by activation viral mimicry response. EZH2抑制和5-氮杂胞苷通过激活病毒模拟反应增强pten缺陷胶质母细胞瘤的抗肿瘤免疫。
IF 10.3 1区 医学
Journal for Immunotherapy of Cancer Pub Date : 2025-06-13 DOI: 10.1136/jitc-2025-011650
Dandan Zhu, Zeying Li, Huolun Feng, Jiabin Zheng, Xiao Xiao, Zuda Huang, Liangying Zheng, Jieqing Guo, Fa Ling, Yong Li, Fan Xing
{"title":"EZH2 inhibition and 5-azacytidine enhance antitumor immunity in PTEN-deficient glioblastoma by activation viral mimicry response.","authors":"Dandan Zhu, Zeying Li, Huolun Feng, Jiabin Zheng, Xiao Xiao, Zuda Huang, Liangying Zheng, Jieqing Guo, Fa Ling, Yong Li, Fan Xing","doi":"10.1136/jitc-2025-011650","DOIUrl":"10.1136/jitc-2025-011650","url":null,"abstract":"<p><strong>Background: </strong>PTEN-deficient glioblastoma (GBM) is characterized by an immunosuppressive tumor microenvironment (TME), therapeutic resistance, and poor prognosis. Emerging evidence suggests that dysregulation of the endogenous retrovirus (ERV)-MAVS-IFN pathway may contribute to immune evasion in cancer, but its role in PTEN-deficient GBM remains unclear.</p><p><strong>Methods: </strong>Using flow cytometry and single-cell RNA sequencing, we analyzed the immune landscape of PTEN-deficient GBM. We evaluated the effects of 5-azacytidine (5-AZA) monotherapy and its combination with EZH2 inhibition (EZH2i) on ERV reactivation, type I interferon (IFN) responses, and TME remodeling. Mechanistic studies focused on H3K27me3-mediated epigenetic regulation of ERV expression.</p><p><strong>Results: </strong>We found that PTEN deficiency suppresses type I IFN responses by impairing viral mimicry through dysregulation of the ERV-MAVS-IFN pathway, thereby sustaining an immunosuppressive TME. While 5-AZA alone failed to reactivate ERVs or overcome therapeutic resistance, combining it with EZH2i synergistically restored robust type I IFN signaling. This combination therapy reduced H3K27me3 levels, promoting ERV transcriptional activation and enhancing 5-AZA-induced viral mimicry. Consequently, the dual treatment reprogrammed the TME to boost antitumor immunity and suppress tumor progression.</p><p><strong>Conclusions: </strong>Our study demonstrates that PTEN-deficient GBM evades immune surveillance by suppressing the ERV-MAVS-IFN axis. The combination of EZH2i and 5-AZA overcomes this resistance by epigenetically reactivating viral mimicry, offering a promising therapeutic strategy to enhance antitumor immunity and improve outcomes in patients with PTEN-deficient GBM.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293767","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}
引用次数: 0
Anti-CTGF/PD-1 bispecific antibody Y126S restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancer. 抗ctgf /PD-1双特异性抗体Y126S抑制胰腺癌组织增生和免疫抑制微环境
IF 10.3 1区 医学
Journal for Immunotherapy of Cancer Pub Date : 2025-06-13 DOI: 10.1136/jitc-2025-012144
Shiru Chen, Yuchong Zhao, Mengdie Cao, Wang Peng, Hai Huang, Yilei Yang, Jingwen Liang, Wei Chen, Shuya Bai, Qiaodan Zhou, Jiamei Jiang, Yilin Gu, Ronghua Wang, Bin Cheng
{"title":"Anti-CTGF/PD-1 bispecific antibody Y126S restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancer.","authors":"Shiru Chen, Yuchong Zhao, Mengdie Cao, Wang Peng, Hai Huang, Yilei Yang, Jingwen Liang, Wei Chen, Shuya Bai, Qiaodan Zhou, Jiamei Jiang, Yilin Gu, Ronghua Wang, Bin Cheng","doi":"10.1136/jitc-2025-012144","DOIUrl":"https://doi.org/10.1136/jitc-2025-012144","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic and immunosuppressive tumor microenvironment (TME), limiting the efficacy of immune checkpoint inhibitors such as anti-programmed cell death 1 (PD-1).</p><p><strong>Methods: </strong>This study aimed to evaluate the therapeutic potential of Y126S, a recombinant IgG1/IgG2 hybrid bispecific antibody (BsAb), in reshaping the immunotherapy-resistant TME in PDAC. Orthotopic PDAC and KPC (Kras<sup>LSL-G12D/+</sup>; Trp53<sup>LSL-R172H/+</sup>; Pdx1-Cre) mouse models were established and treated with Y126S, α-connective tissue growth factor (CTGF), α-PD-1, or a combination of α-CTGF and α-PD-1. TME remodeling, antibody distribution, and therapeutic efficacy were assessed using flow cytometry, immunohistochemical/Masson staining, atomic force microscopy, positron emission tomography (PET) imaging, distribution analysis, and other experimental techniques.</p><p><strong>Results: </strong>Here, Y126S was characterized <i>in vitro</i> and its antitumor efficacy was evaluated and validated in orthotopic PDAC mice and KPC mouse models. Notably, Y126S significantly remodeled the TME and demonstrated superior tumor-specific accumulation compared with single α-PD-1 treatment, leading to markedly enhanced antitumor efficacy relative to its parental antibodies or their combination. Mechanistically, Y126S suppressed cancer-associated fibroblasts (CAFs) activation, reduced collagen deposition, and downregulated programmed cell death ligand 1 (PD-L1) expression on CAFs by targeting CTGF and enhanced the anti-PD-1-mediated reinvigoration of cytotoxic CD8<sup>+</sup> T cells, thereby establishing a less desmoplastic and potent tumor-killing microenvironment.</p><p><strong>Conclusions: </strong>Our findings highlight the potential of Y126S as a promising BsAb-based immunotherapy strategy for PDAC by remodeling the desmoplastic and immunosuppressive TME.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Correction: Novel post-translational modification learning signature reveals B4GALT2 as an immune exclusion regulator in lung adenocarcinoma. 修正:新的翻译后修饰学习特征显示B4GALT2在肺腺癌中是一种免疫排斥调节因子。
IF 10.3 1区 医学
Journal for Immunotherapy of Cancer Pub Date : 2025-06-12 DOI: 10.1136/jitc-2024-010787corr1
{"title":"Correction: Novel post-translational modification learning signature reveals B4GALT2 as an immune exclusion regulator in lung adenocarcinoma.","authors":"","doi":"10.1136/jitc-2024-010787corr1","DOIUrl":"10.1136/jitc-2024-010787corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293765","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}
引用次数: 0
Exploring the tumor microenvironment in diffuse intrinsic pontine glioma: immunological insights and therapeutic challenges. 探讨弥漫性脑桥内胶质瘤的肿瘤微环境:免疫学见解和治疗挑战。
IF 10.3 1区 医学
Journal for Immunotherapy of Cancer Pub Date : 2025-06-12 DOI: 10.1136/jitc-2025-012009
Bieke Van den Ende, Matteo Riva, Frederik De Smet, Sandra Jacobs, Esther Hulleman, An Coosemans
{"title":"Exploring the tumor microenvironment in diffuse intrinsic pontine glioma: immunological insights and therapeutic challenges.","authors":"Bieke Van den Ende, Matteo Riva, Frederik De Smet, Sandra Jacobs, Esther Hulleman, An Coosemans","doi":"10.1136/jitc-2025-012009","DOIUrl":"10.1136/jitc-2025-012009","url":null,"abstract":"<p><p>Diffuse intrinsic pontine glioma (DIPG) is a rare and highly aggressive pediatric brain tumor with a median survival of less than 12 months. The tumor arises in the pons, making surgical resection unfeasible and limiting treatment options to palliative radiation, which offers minimal survival benefit. One of the major challenges in treating DIPG is the poorly understood tumor immune microenvironment, which has hindered the development of effective immunotherapies. DIPG tumors are considered to be immunologically cold with limited immune cell infiltration. Recent studies have begun to reveal the complex and heterogeneous immune landscape of DIPG, highlighting distinct immunological subgroups. This review aims to provide a comprehensive overview of the immune landscape of DIPG based on the latest insights, identify research gaps, and suggest potential areas for future investigation to improve treatment outcomes for patients with DIPG.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293766","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}
引用次数: 0
Phase II study of rucaparib and nivolumab in patients with leiomyosarcoma. 鲁卡帕尼和纳武单抗治疗平滑肌肉瘤的II期研究。
IF 10.3 1区 医学
Journal for Immunotherapy of Cancer Pub Date : 2025-06-12 DOI: 10.1136/jitc-2025-012020
Sujana Movva, Kenneth Seier, Martina Bradic, Karmelina Charalambous, Evan Rosenbaum, Ciara M Kelly, Seth M Cohen, Martee L Hensley, Viswatej Avutu, Lauren B Banks, Jason E Chan, Ping Chi, Sandra D'Angelo, Mark A Dickson, Mrinal M Gounder, Mary L Keohan, Robert G Maki, Angela Green, Vicky Makker, Maria M Rubinstein, Sara Saunds, Jae-Mun Cho, Robert A Lefkowitz, Joseph Erinjeri, Li-Xuan Qin, Ronak Shah, Phillip Wong, William Tap
{"title":"Phase II study of rucaparib and nivolumab in patients with leiomyosarcoma.","authors":"Sujana Movva, Kenneth Seier, Martina Bradic, Karmelina Charalambous, Evan Rosenbaum, Ciara M Kelly, Seth M Cohen, Martee L Hensley, Viswatej Avutu, Lauren B Banks, Jason E Chan, Ping Chi, Sandra D'Angelo, Mark A Dickson, Mrinal M Gounder, Mary L Keohan, Robert G Maki, Angela Green, Vicky Makker, Maria M Rubinstein, Sara Saunds, Jae-Mun Cho, Robert A Lefkowitz, Joseph Erinjeri, Li-Xuan Qin, Ronak Shah, Phillip Wong, William Tap","doi":"10.1136/jitc-2025-012020","DOIUrl":"10.1136/jitc-2025-012020","url":null,"abstract":"<p><strong>Background: </strong>Objective responses to immune checkpoint inhibitors (ICI) in leiomyosarcoma (LMS) are rare. Response rates may be increased by combination with other drugs known to promote immune infiltration, such as poly(ADP-ribose) polymerase (PARP) inhibitors, which have led to benefit in <i>BRCA</i>-altered uterine LMS. We therefore evaluated the combination of a PARP inhibitor, rucaparib, and the anti-programmed death receptor-1 monoclonal antibody, nivolumab, in patients with advanced LMS and investigated its effects on the tumor immune microenvironment.</p><p><strong>Methods: </strong>This was an open-label, single-center, single-arm, phase II study in patients with advanced refractory LMS. Full protocol available Patients were treated with rucaparib 600 mg orally, two times daily, continuously and nivolumab 480 mg intravenously on day 1 of a 28-day cycle. Re-staging scans were performed every 8 weeks. Blood and tissue samples were collected at baseline and at week 8 on treatment. The primary objective was the best objective response rate by 24 weeks using Response Evaluation Criteria in Solid Tumour (RECIST V.1.1). Secondary objectives included treatment-related toxicity, progression-free survival, overall survival, and changes in immune pathways in blood and tumor.</p><p><strong>Results: </strong>20 patients with LMS were enrolled. There was one partial response (PR) (5%) in a patient with uterine LMS and a somatic <i>BRCA</i> deep deletion. 19 (95%) patients had a treatment-related adverse event (TRAE) and 7 (35%) had a grade 3 or higher TRAE. Interferon (IFN) α and γ hallmark pathways were more highly expressed in patients who derived benefit from treatment (at least stable disease by 16 weeks) vs those who did not in both baseline (adjusted p=0.005 for IFN-α, 0.03 for IFN-γ) and on-treatment biopsies (adjusted p=0.0002 for IFN-α, 0.0001 for IFN-γ), but the abundance of tumor immune cell populations did not differ between these groups at either time point.</p><p><strong>Conclusion: </strong>The addition of a PARP inhibitor did not improve the efficacy of ICI in LMS. Adverse events, especially due to overlapping toxicities, were frequent and often led to dose delays and modifications.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293769","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}
引用次数: 0
Predictive value of preclinical models for CAR-T cell therapy clinical trials: a systematic review and meta-analysis. CAR-T细胞治疗临床试验的临床前模型的预测价值:系统回顾和荟萃分析。
IF 10.3 1区 医学
Journal for Immunotherapy of Cancer Pub Date : 2025-06-12 DOI: 10.1136/jitc-2025-011698
David Andreu-Sanz, Lisa Gregor, Emanuele Carlini, Daniele Scarcella, Carsten Marr, Sebastian Kobold
{"title":"Predictive value of preclinical models for CAR-T cell therapy clinical trials: a systematic review and meta-analysis.","authors":"David Andreu-Sanz, Lisa Gregor, Emanuele Carlini, Daniele Scarcella, Carsten Marr, Sebastian Kobold","doi":"10.1136/jitc-2025-011698","DOIUrl":"10.1136/jitc-2025-011698","url":null,"abstract":"<p><p><b>Background</b> Experimental mouse models are indispensable for the preclinical development of cancer immunotherapies, whereby complex interactions in the tumor microenvironment can be somewhat replicated. Despite the availability of diverse models, their predictive capacity for clinical outcomes remains largely unknown, posing a hurdle in the translation from preclinical to clinical success. <b>Methods</b> This study systematically reviews and meta-analyzes clinical trials of chimeric antigen receptor (CAR)-T cell monotherapies with their corresponding preclinical studies. Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a comprehensive search of PubMed and ClinicalTrials.gov was conducted, identifying 422 clinical trials and 3,157 preclinical studies. From these, 105 clinical trials and 180 preclinical studies, accounting for 44 and 131 distinct CAR constructs, respectively, were included. <b>Results</b> Patients' responses varied based on the target antigen, expectedly with higher efficacy and toxicity rates in hematological cancers. Preclinical data analysis revealed homogeneous and antigen-independent efficacy rates. Our analysis revealed that only 4% (n=12) of mouse studies used syngeneic models, highlighting their scarcity in research. Three logistic regression models were trained on CAR structures, tumor entities, and experimental settings to predict treatment outcomes. While the logistic regression model accurately predicted clinical outcomes based on clinical or preclinical features (Macro F1 and area under the curve (AUC)>0.8), it failed in predicting preclinical outcomes from preclinical features (Macro F1<0.5, AUC<0.6), indicating that preclinical studies may be influenced by experimental factors not accounted for in the model. <b>Conclusion</b> These findings underscore the need to better understand the experimental factors enhancing the predictive accuracy of mouse models in preclinical settings.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293770","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}
引用次数: 0
ADRB2 inhibition suppresses cancer immune evasion by regulating tumor SOX10-PD-L1 axis and T cell function. ADRB2抑制通过调节肿瘤SOX10-PD-L1轴和T细胞功能抑制癌症免疫逃避。
IF 10.3 1区 医学
Journal for Immunotherapy of Cancer Pub Date : 2025-06-12 DOI: 10.1136/jitc-2025-011611
Yu Zhang, Feng Yu, Jing Ouyang, Panpan Liu, Yingying Dai, Yang Wang, Hanying Yi, Shiyu Wang, Dongbo Liu, Kun Song, Wenwu Pei, Ziyang Hong, Wei Zhang, Weihua Huang, Gan Zhou, Shan Cao, Howard McLeod, Cong Peng, Ling Chen, Yijing He
{"title":"ADRB2 inhibition suppresses cancer immune evasion by regulating tumor SOX10-PD-L1 axis and T cell function.","authors":"Yu Zhang, Feng Yu, Jing Ouyang, Panpan Liu, Yingying Dai, Yang Wang, Hanying Yi, Shiyu Wang, Dongbo Liu, Kun Song, Wenwu Pei, Ziyang Hong, Wei Zhang, Weihua Huang, Gan Zhou, Shan Cao, Howard McLeod, Cong Peng, Ling Chen, Yijing He","doi":"10.1136/jitc-2025-011611","DOIUrl":"10.1136/jitc-2025-011611","url":null,"abstract":"<p><strong>Background: </strong>Chronic stress is known to promote cancer progression, in part by modulating immune responses through the β<sub>2</sub>-adrenergic receptor (ADRB2). Inhibiting ADRB2 with β-blockers has demonstrated potential in boosting the effectiveness of immune checkpoint inhibitors across a spectrum of cancers, yet the precise mechanisms remain to be fully elucidated.</p><p><strong>Methods: </strong>In vivo and in vitro experiments were performed to evaluate the role of ADRB2 in melanoma models, including its effects on T cells. RNA sequencing analysis highlighted the importance of the transcription factor SRY-related HMG-box 10 (SOX10), which transcriptionally regulates programmed death-ligand 1 (PD-L1). This regulatory role was further validated using luciferase reporter assays and chromatin immunoprecipitation-PCR assays. Mechanistic studies focused on ADRB2 signaling through protein kinase A (PKA) and its downstream target SOX10. To investigate SOX10's role in mediating the effects of ADRB2, knockdown and overexpression experiments were conducted. Additionally, similar studies in colorectal cancer (CRC) models confirmed the conserved function of the ADRB2-SOX10-PD-L1 axis.</p><p><strong>Results: </strong>This study explores the role of ADRB2 in regulating tumor PD-L1 expression and T cell functionality, offering insights for cancer immunotherapy. Clinical data revealed that patients with melanoma with high ADRB2 expression responded better to programmed cell death protein 1 inhibitors. In melanoma models, ADRB2 inhibition reduced PD-L1 expression, enhanced T cell infiltration, and promoted antitumor immunity, while ADRB2 activation had the opposite effect. Mechanistically, ADRB2 signaling through PKA upregulated SOX10, which transcriptionally modulates PD-L1. SOX10 knockdown replicated the effects of ADRB2 inhibition, while SOX10 overexpression reversed them. Similar findings in CRC models confirmed the conserved role of the ADRB2-SOX10-PD-L1 axis. Targeting ADRB2 and SOX10 may enhance immune checkpoint inhibitor efficacy in cancer treatment.</p><p><strong>Conclusions: </strong>These findings underscore the potential of ADRB2 and SOX10 as therapeutic targets for mitigating stress-induced immunosuppression and for augmenting the effectiveness of immunotherapies in a variety of cancer types.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293686","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}
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