Journal for Immunotherapy of Cancer最新文献

{"title":"Corticosteroid premedication on anti-tumor effect of immune checkpoint blockade in murine hepatocellular carcinoma models.","authors":"Ying-Chun Shen, Nai-Wen Chang, Ching-Ping Yeh, Wan-Ying Lin, Ming-Feng Wei, Da-Liang Ou, Chia-Lang Hsu, Ann-Lii Cheng","doi":"10.1136/jitc-2024-009704","DOIUrl":"10.1136/jitc-2024-009704","url":null,"abstract":"<p><strong>Background and aims: </strong>Corticosteroid is effective in alleviating immune-related adverse events (irAEs) of immune checkpoint blockade (ICB). However, prophylactic use of corticosteroid to prevent irAEs is not recommended due to a looming concern that it may attenuate anti-tumor effect of ICB. This study aims to investigate whether corticosteroid premedication may compromise anti-tumor efficacy of dual ICB, a regimen that may cause significant irAEs.</p><p><strong>Methods: </strong>Orthotopic BNL 1MEA.7R.1 and subcutaneous Hepa1-6 syngeneic hepatocellular carcinoma (HCC) models were used. Low-dose (LD; 10 µg) or high-dose (HD; 200 µg) dexamethasone (Dexa) was intraperitoneally administered before each dose of anti-CTLA-4 and anti-PD-1. Tumor shrinkage, T cell priming, cytokine quantitation, as well as cytotoxicity and single-cell RNA-sequencing (scRNA-seq) of tumor-infiltrating T cells were assessed.</p><p><strong>Results: </strong>In the orthotopic model, dual immune checkpoint blockade (dICB) plus phosphate buffered saline (PBS) significantly reduced the mean tumor weight (adjusted for SE) (0.73±0.18 g vs 2.45±0.54 g; p=0.03), while neither LD nor HD Dexa premedication affected dICB-induced tumor shrinkage. In the subcutaneous model, dICB plus PBS or LD Dexa yielded a complete tumor response (CR) rate of 100%, while dICB plus HD Dexa yielded a CR rate of 85.7% (p>0.05, comparing to dICB plus PBS). ScRNA-seq analysis demonstrates that Dexa did not affect dICB-induced reduction of major clusters of exhausted CD4+ and CD8+ T cells but halved dICB-induced expansion of effector memory CD8+ T cells. Nevertheless, Dexa premedication, regardless of dosage, did not diminish dICB-induced T cell priming, cytokine production, or cytotoxicity of tumor-infiltrating CD8+ T cells.</p><p><strong>Conclusion: </strong>Corticosteroid premedication does not significantly compromise anti-tumor efficacy of dICB treatment in murine HCC models. These results suggest that clinical investigations of prophylactic corticosteroids to alleviate severe irAEs may be feasible.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468007","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":"Phase I dose-escalation and pharmacodynamic study of STING agonist E7766 in advanced solid tumors.","authors":"Jason J Luke, David J Pinato, Dejan Juric, Patricia LoRusso, Peter J Hosein, Anupam M Desai, Robert Haddad, María de Miguel, Andrés Cervantes, Won Seog Kim, Aurélien Marabelle, Yan Zhang, Yuanxin Rong, Xiaobin Yuan, Stéphane Champiat","doi":"10.1136/jitc-2024-010511","DOIUrl":"10.1136/jitc-2024-010511","url":null,"abstract":"<p><p>E7766 is a novel stimulator of interferon genes (STING) agonist, capable of potent activation of immune cells and generating strong antitumor response in preclinical murine tumor models. Here we present the safety, efficacy, and biomarker results of the first-in-human phase I/Ib study of intratumoral E7766 in patients with advanced solid tumors. Eligible patients with relapsing/refractory cancers (n=24) were enrolled in dose-escalating cohorts to receive intratumoral injections of E7766 from 75 to 1000 µg. The most frequent treatment-related treatment-emergent adverse events were chills (50.0%; 85.7%), fever (40.0%; 85.7%), and fatigue (30.0%; 35.7%) in patients who received non-visceral and visceral injections, respectively. Eight patients (33.3%) achieved stable disease as their best response per modified Response Evaluation Criteria In Solid Tumors version 1.1 with variability between injected and non-injected lesions. Plasma levels of IFN-α, IFN-β, IFN-γ, TNF-α, IL-6, IP-10, MCP1, and MIP1b transiently increased in all evaluable patients within 10 hours postinjection, then dropped to baseline levels. Levels of blood and tumor gene expression increased in most interferon-related and STING genes tested. Further increases in programmed death ligand 1 and cluster of differentiation 8 expression at both the RNA and protein levels were also observed in some patients across dose levels. In total, E7766 generated on-target pharmacodynamic effects in patients with solid tumors. Further exploration in a homogeneous patient population is necessary to assess efficacy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11842995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468105","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 adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation.","authors":"Fei Sun, Fangzhen Yao, Chunting Zeng, Yang Zhao, Bishan Liang, Shaowei Li, Yawen Wang, Qijing Wu, Yulu Shi, Zhiqi Yao, Jiao Wang, Yu Jiang, Chunhui Gu, Qiong Huang, Wangjun Liao, Na Huang, Chunlin Wang, Xiaoxiang Rong, Jing Wu, Yujing Tan, Jianjun Peng, Yong Li, Min Shi","doi":"10.1136/jitc-2024-010126","DOIUrl":"10.1136/jitc-2024-010126","url":null,"abstract":"<p><strong>Background: </strong>Patients with microsatellite stable (MSS) colorectal cancer (CRC) often display resistance to immunotherapy. Epidermal growth factor receptor (EGFR)-targeted therapies have shown potential in enhancing immunotherapy, yet clinical benefits remain unfulfilled, which may relate to inadequate patient stratification.</p><p><strong>Methods: </strong>Circulating tumor cells and tumor tissues were collected from multicenter cohorts of patients with CRC receiving cetuximab to analyze EGFR variant type III (EGFRvIII) expression and immune infiltration. Syngeneic mouse models of EGFRvIII CRC were used to investigate the combined efficacy of adenosine inhibition and antiprogrammed cell death protein 1 (anti-PD-1).</p><p><strong>Results: </strong>EGFRvIII mutations are found in about 10% of MSS CRC and are associated with poor response to cetuximab therapy. EGFRvIII-mutated patients with CRC exhibit an adenosine-mediated immunosuppressive tumor microenvironment (TME) subtype. Combination therapy with adenosine inhibitors remodels the TME, reversing cetuximab resistance and enhancing anti-PD-1 efficacy in EGFRvIII CRC.</p><p><strong>Conclusions: </strong>Our findings identified EGFRvIII-positive CRC as a distinct subtype characterized by adenosine-mediated immunosuppressive TME. Targeting adenosine significantly improved the efficacy of anti-PD-1 in MSS CRC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414342","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":"Correction: Peritumoral administration of IFNβ upregulated mesenchymal stem cells inhibits tumor growth in an orthotopic, immunocompetent rat glioma model.","authors":"","doi":"10.1136/jitc-2019-000164corr1","DOIUrl":"10.1136/jitc-2019-000164corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414341","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":"Radiomic analysis of patient and interorgan heterogeneity in response to immunotherapies and BRAF-targeted therapy in metastatic melanoma.","authors":"Alexandra G Tompkins, Zane N Gray, Rebekah E Dadey, Serafettin Zenkin, Nasim Batavani, Sarah Newman, Afsaneh Amouzegar, Murat Ak, Nursima Ak, Taha Yasin Pak, Vishal Peddagangireddy, Priyadarshini Mamindla, Mohammadreza Amjadzadeh, Sarah Behr, Amy Goodman, Darcy L Ploucha, John M Kirkwood, Hassane M Zarour, Yana G Najjar, Diwakar Davar, Curtis Tatsuoka, Rivka R Colen, Jason John Luke, Riyue Bao","doi":"10.1136/jitc-2024-009568","DOIUrl":"10.1136/jitc-2024-009568","url":null,"abstract":"<p><p>Variability in treatment response may be attributable to organ-level heterogeneity in tumor lesions. Radiomic analysis of medical images can elucidate non-invasive biomarkers of clinical outcome. Organ-specific radiomic comparison across immunotherapies and targeted therapies has not been previously reported. We queried the UPMC Hillman Cancer Center registry for patients with metastatic melanoma (MEL) treated with immune checkpoint inhibitors (ICI) (anti-programmed cell death protein-1 (PD-1)/cytotoxic T-lymphocyte associated protein 4 (CTLA-4) (ipilimumab+nivolumab; I+N) or anti-PD-1 monotherapy) or BRAF-targeted therapy. The best overall response was measured using Response Evaluation Criteria in Solid Tumors V.1.1. Lesions were segmented into discrete volume-of-interest with 400 radiomics features extracted. Overall and organ-specific machine-learning models were constructed to predict disease control (DC) versus progressive disease (PD) using XGBoost. 291 patients with MEL were identified, including 242 ICI (91 I+N, 151 PD-1) and 49 BRAF. 667 metastases were analyzed, including 541 ICI (236 I+N, 305 PD-1) and 126 BRAF. Across cohorts, baseline demographics included 39-47% women, 24%-29% M1C, 24-46% M1D, and 61-80% with elevated lactate dehydrogenase. Among ICI patients experiencing DC, the organs with the greatest reduction were liver (-66%±8%; mean±SEM) and lung (-63%±5%). For patients with multiple same-organ target lesions, the highest interlesion heterogeneity was observed in brain among patients who received ICI while no intraorgan heterogeneity was observed in BRAF. 221 ICI patients were included for radiomic modeling, consisting of 86 I+N and 135 PD-1. Models consisting of optimized radiomic signatures classified DC/PD across I+N (area under curve (AUC)=0.85) and PD-1 (0.71) and within individual organ sites (AUC=0.72~0.94). Integration of clinical variables improved the models' performance. Comparison of models between treatments and across organ sites suggested mostly non-overlapping DC or PD features. Skewness, kurtosis, and informational measure of correlation (IMC) were among the radiomic features shared between overall response models. Kurtosis and IMC were also used by multiple organ-site models. In conclusion, differential organ-specific response was observed across BRAF and ICI with within organ heterogeneity observed for ICI but not for BRAF. Radiomic features of organ-specific response demonstrated little overlap. Integrating clinical factors with radiomics improves the prediction of disease course outcome and prediction of tumor heterogeneity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407748","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":"Acetyltransferase NAT10 inhibits T-cell immunity and promotes nasopharyngeal carcinoma progression through DDX5/HMGB1 axis.","authors":"Haijing Xie, Kaiwen Zhang, Haimeng Yin, Siyu Zhang, Si Pan, Rui Wu, Yumo Han, Yi Xu, Weihong Jiang, Bo You","doi":"10.1136/jitc-2024-010301","DOIUrl":"10.1136/jitc-2024-010301","url":null,"abstract":"<p><strong>Background: </strong>Immunosuppression significantly contributes to treatment failure in nasopharyngeal carcinoma (NPC). Messenger RNA (mRNA) modifications such as methylation and acetylation play crucial roles in immunosuppression. However, N4-acetylcytidine (ac4C), the only acetylation modification event has rarely been studied in NPC.</p><p><strong>Methods: </strong>First, clinical tissue samples and nude mouse models were used to explore the expression of N-acetyltransferase 10 (NAT10) in NPC and its influence on it. Second, The Cancer Genome Atlas immune database and transgenic mouse peripheral blood immune cell panel were used to verify the immune cells mainly affected by NAT10. Then, NAT10 ac4C acetylation modification and expression of significantly upregulated transcription factors were explored by acetylated RNA immunoprecipitation sequence binding to RNA sequencing. Then, the downstream regulatory genes of CCAAT enhancer binding protein γ (CEBPG), dead box helicase 5 (DDX5) and helicase-like transcription factors (HLTF) were analyzed by luciferase report and chromatin Immunoprecipitation. Finally, the effect of inhibition of NAT10 on anti-programmed cell death protein 1 (PD-1) treatment sensitivity was verified by animal models.</p><p><strong>Results: </strong>In this study, we aimed to explore the role of NAT10, the enzyme responsible for ac4C modification, in NPC progression and patient prognosis. Elevated NAT10 promoted NPC progression and correlated with poor prognosis in patients with NPC. NAT10-mediated ac4C modification of <i>CEBPG</i>, <i>DDX5</i>, and <i>HLTF</i> mRNA improved their stability and translation efficiency, with the NAT10/ac4C/DDX5 axis upregulating high mobility group box 1 (HMGB1) and inhibiting CD4+ and CD8+ T cells. Inhibition of NAT10 increased the sensitivity to PD-1 therapy. Additionally, HLTF was found to transcriptionally regulate NAT10, indicating the formation of an HLTF-NAT10 positive feedback loop.</p><p><strong>Conclusions: </strong>Our study elucidates the mechanism by which the <i>NAT10/DDX5/HMGB1</i> axis promotes the immunosuppression of NPC by promoting T-cell dysfunction. In addition, NAT10 knockdown can enhance anti-PD-1 treatment sensitivity as a combination therapy for NPC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407251","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":"Efficacy and safety of nivolumab plus ipilimumab in patients with metastatic variant histology (non-clear cell) renal cell carcinoma.","authors":"Mohammad Jad Moussa, Jaanki Khandelwal, Nathaniel R Wilson, Kiran L Malikayil, Devaki Shilpa Surasi, Tharakeswara K Bathala, Yiyun Lin, Priya Rao, Pheroze Tamboli, Kanishka Sircar, Helen Ajufo, Khaled M Elsayes, Amishi Shah, Andrew C Johns, Sangeeta Goswami, Elshad Hasanov, Eric Jonasch, Pavlos Msaouel, Matthew T Campbell, Omar Alhalabi, Nizar M Tannir","doi":"10.1136/jitc-2024-010958","DOIUrl":"10.1136/jitc-2024-010958","url":null,"abstract":"<p><strong>Background: </strong>Nivolumab plus ipilimumab (nivo/ipi) is a standard of care first-line (1 L) therapy for patients with metastatic clear-cell renal cell carcinoma (ccRCC), but its role in patients with metastatic, non-ccRCC has not been fully defined. We report a single-institution experience with nivo/ipi in non-ccRCC.</p><p><strong>Methods: </strong>Between November 2017 and February 2024, 55 patients with metastatic non-ccRCC received nivo/ipi at MD Anderson Cancer Center. The tumor response was assessed by blinded radiologists using RECIST v1.1. The overall response rate (ORR), progression-free survival (PFS), PFS milestone, duration of response (DoR), and overall survival (OS) were determined. Next-generation sequencing (NGS) was performed on available tumor specimens.</p><p><strong>Results: </strong>Twenty-five (45.5%) patients had papillary histology (pRCC), 12 (21.8%) patients had chromophobe (chRCC), and 18 (32.7%) patients had unclassified RCC (uRCC). Fifty-two (94.5%) patients received nivo/ipi in 1 L. Sarcomatoid features (SF) were found in 20 (36.4%) cases. ORR was 48% (12/25) in pRCC, 25% (3/12) in chRCC (all 3 cases had SF), 27.8% (5/18) in uRCC, and 55% (11/20) across histologies with SF.The median PFS was 10.6 months (95% CI: 2.8 to 22.8) in pRCC, 3.6 months (95% CI: 0.9 - NE) in chRCC, and 3 months (95% CI: 2.1 to 7) in uRCC; 6-month milestone PFS was 56% (95% CI: 36.3 to 75.7), 41.7% (95% CI: 22 to 61.3), and 38.9% (95% CI: 21.7 to 56.1) in pRCC, chRCC, and uRCC, respectively. The median DoR for the entire cohort was 8.5 months (95% CI: 8 - NE). The median OS was 36.7 months (95% CI: 11.5 to 54.8) in pRCC, 25.7 months (95% CI: 0.9 - NE) in chRCC, and 11.1 months (95% CI: 6.5 - NE) in uRCC.Ten (18.2%) patients discontinued treatment due to treatment-related adverse events (AEs). Grade 3/4 immune-mediated AEs were noted in 17 (30.9%) patients. We performed NGS on 26 cases: <i>TP53</i> (42%), <i>PTEN</i> (23%), and <i>TERT</i> (23%) alterations were most frequently found, with <i>TERT</i> and <i>TP53</i> mutations enriched in pRCC and chRCC, respectively.</p><p><strong>Conclusion: </strong>Nivo/ipi produced favorable outcomes in patients with pRCC supporting its use as 1 L therapy. Responses in patients with chRCC were noted exclusively with SF. Despite achieving an ORR of 27.8% with nivo/ipi, patients with uRCC had short PFS and inferior OS.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407746","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":"CD56^bright cytokine-induced memory-like NK cells and NK-cell engagers synergize against non-small cell lung cancer cancer-stem cells.","authors":"Maria L Guevara Lopez, Ann Gebo, Monica Parodi, Stefano Persano, Josephine Maus-Conn, Maria Cristina Mingari, Fabrizio Loiacono, Paola Orecchia, Simona Sivori, Claudia Cantoni, Marco Gentili, Federica Facchinetti, Riccardo Ferracini, Daniel A Vallera, Martin Felices, Giulia Bertolini, Marco Pravetoni, Luca Roz, Massimo Vitale","doi":"10.1136/jitc-2024-010205","DOIUrl":"10.1136/jitc-2024-010205","url":null,"abstract":"<p><strong>Background: </strong>Due to their enhanced responsiveness and persistence, cytokine-induced memory-like (CIML)-natural killer (NK) cells have emerged as new immunotherapeutic tools against malignancies. However, their effects on tumor-cell spread and metastases in solid tumors remain poorly investigated. Moreover, a clear identification of the most effective CIML-NK subsets, especially in controlling cancer stem cells (CSC), is still lacking.</p><p><strong>Methods: </strong>We performed combined phenotypical and functional analyses of CIML-NK cell subsets, either selected by flow-cytometry gating, or generated from sorted CD56^bright/CD56^dim NK cells.By co-culture experiments, we analyzed the effect of CIML-NK cells on non-small cell lung cancer (NSCLC) cell spheroids, or patient-derived xenografts (PDX), assessing changes in their CSC content, tumorigenicity, and/or tumor disseminating capability in vivo. CIML-NK cells were also infused in PDX-bearing mice to validate their effect on the CSC dissemination from the PDX to the lungs.Finally, we generated and functionally analyzed CIML-NK cells from patients with stages I/III NSCLC (n=6).</p><p><strong>Results: </strong>We show that CIML-NK cells exert antitumor activity mostly through their CD56^bright cell subset, which greatly expands during CIML differentiation. Compared with NK cells conventionally activated with interleukin-2, CIML-NK cells express lower levels of check-point receptors, TIGIT and TIM3, and higher effector functions against NSCLC cells from PDX, and against in vitro-generated tumor spheroids. Remarkably, CIML-NK cells also significantly reduce the CSC-containing CD133⁺ cell subpopulation within spheroids and PDX, and limit tumor cell tumorigenicity and ability to disseminate CSCs from primary tumors to distant sites. Sorting experiments on CIML or tumor cell subsets reveal that CD56^bright cells drive most of this anti-CSC activity, and suggest that such functional advantage could be related to increased expression of LFA-1 and ICAM-1 on CD56^bright cells and CSCs, respectively. We also show that the tri-specific killer cell engager (TriKE) 1615133 significantly enhances CIML-NK cell activity against CSCs. Finally, we demonstrate that CIML-NK cells, capable of killing autologous tumor cells and responding to the 1615133 TriKE, could be induced from patients with NSCLC.</p><p><strong>Conclusions: </strong>Our study discloses for the first time the therapeutic potential of CIML-NK cells in controlling CSCs and metastatic spread, highlighting the role of the CD56^bright subset expansion and 1615133 TriKE for optimizing CIML-NK-based therapies against metastatic tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407738","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":"Correction: Novel banana lectin CAR-T cells to target pancreatic tumors and tumor-associated stroma.","authors":"","doi":"10.1136/jitc-2022-005891corr1","DOIUrl":"10.1136/jitc-2022-005891corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399217","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":"4-1BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor models.","authors":"Eneko Garate-Soraluze, Irantzu Serrano-Mendioroz, Leticia Fernández-Rubio, Carlos E De Andrea, Celia Barrio-Alonso, Claudia Del Pilar Herrero, Alvaro Teijeira, Carlos Luri-Rey, Christina Claus, Tamara Tanos, Christian Klein, Pablo Umana, Antonio Rullan, Jon Ander Simón, María Collantes, Paloma Sánchez-Mateos, Ignacio Melero, Maria E Rodriguez-Ruiz","doi":"10.1136/jitc-2024-009852","DOIUrl":"10.1136/jitc-2024-009852","url":null,"abstract":"<p><strong>Background: </strong>Ionizing radiation (IR) is a double-edged sword for immunotherapy as it may have both immunosuppressive and immunostimulatory effects. The biological effects of IR on the tumor microenvironment (TME) are a key factor for this balance. Fibroblast activation protein (FAP) is expressed on the surface of cancer-associated fibroblasts (CAF) in many cancer types and its abundance is associated with the poor immune response to immune-checkpoint-blockade in patients. We hypothesized that IR increases FAP expression in CAFs, therefore the combination of IR with targeted immunomodulators such as an agonistic anti-FAP-4-1BBL fusion protein could enhance the immune-mediated antitumoral effects of these treatments.</p><p><strong>Methods: </strong>The murine transplantable TS/A tumor-cell-line co-engrafted with CAFs was used to investigate increases in FAP expression in tumors following irradiation using immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and multiplex tissue immunofluorescence. One lesion of bilateral tumor-bearing mice was only locally irradiated or combined with weekly injections of the bispecific muFAP-4-1BBL fusion protein (a mouse surrogate for RG7826). Tumor sizes were followed over time and TME was assessed by flow cytometry. Selective monoclonal antibody (mAb)-mediated depletions of immune cell populations, neutralizing interferon alpha/beta receptor 1 (IFNAR-I) IFNAR and interferon (IFN)-γ mAbs and gene-modified mice (4-1BB^-/-) were used to delineate the immune cell subsets and mechanisms required for efficacy. ⁶⁷Ga labeled muFAP-4-1BBL tracked by SPECT-CT was used to study biodistribution. In human colorectal carcinoma samples, the inducibility of FAP expression following radiotherapy was explored by multiplex immunofluorescence.</p><p><strong>Results: </strong>Irradiation of TS/A+CAF tumors in mice showed an increase in FAP levels after local irradiation. A suboptimal radiotherapy regimen in combination with muFAP-4-1BBL attained primary tumor control and measurable abscopal effects. Immune TME landscape analyses showed post-treatment increased infiltration of activated immune cells associated with the combined radioimmunotherapy treatment. Efficacy depended on CD8⁺ T cells, type I IFN, IFN-γ and ability to express 4-1BB. Biodistribution studies of muFAP-4-1BBL indicated enriched tumor targeting to irradiated tumors. Human colorectal cancer samples pre and post irradiation showed enhanced FAP expression after radiotherapy.</p><p><strong>Conclusion: </strong>Increased FAP expression in the TME as a result of radiotherapy can be exploited to target agonist 4-1BB immunotherapy to malignant tumor lesions using an FAP-4-1BBL antibody fusion protein.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399199","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}