Journal for Immunotherapy of Cancer最新文献

{"title":"Microbial Ecosystem Therapeutics 4 (MET4) elicits treatment-specific IgG responses associated with changes in gut microbiota in immune checkpoint inhibitor recipients with advanced solid tumors.","authors":"Matthew K Wong, Giselle M Boukhaled, Eric Armstrong, Rachel Liu, Alya A Heirali, Noelle R Yee, Jinny Tsang, Pavlina Spiliopoulou, Pierre H H Schneeberger, Ben X Wang, Kyla Cochrane, Keith Sherriff, Emma Allen-Vercoe, Lillian L Siu, Anna Spreafico, Bryan Coburn","doi":"10.1136/jitc-2024-010681","DOIUrl":"https://doi.org/10.1136/jitc-2024-010681","url":null,"abstract":"<p><strong>Background: </strong>Gut microbiome modulation has shown promise in its potential to treat cancer in combination with immunotherapy. Mechanistically, the pathways and routes by which gut microbiota may influence systemic and antitumor immunity remain uncertain. Here, we used blood and stool samples from Microbial Ecosystem Therapeutic 4 (MET4)-IO, an early-phase trial testing the safety and engraftment of the MET4 bacterial consortium in immune checkpoint inhibitor recipients, to assess how MET4 may affect systemic immunity.</p><p><strong>Methods: </strong>Circulating antibody responses induced by MET4 were assessed using an antimicrobial antibody flow cytometry assay on pretreatment and post-treatment plasma. Antibody responses were associated with taxonomic changes in stool identified by metagenomic sequencing. Mass cytometry was performed on peripheral blood mononuclear cells to identify shifts in circulating immune subsets associated with antibody responses.</p><p><strong>Results: </strong>Increases in circulating anti-MET4 immunoglobulin G (IgG) responses were measured by flow cytometry post-consortium treatment in MET4 recipients, but not untreated control participants, with five individuals displaying notably higher antibody responses. Stronger IgG responses were associated with greater increases in multiple taxa, including MET4 microbe <i>Collinsella aerofaciens</i>, which was previously linked with immune checkpoint response. However, these taxa were not enriched in the IgG-bound fraction post-MET4 treatment. Greater increases in circulating B cells and FoxP3⁺ CD4⁺ T cells post-MET4 treatment were observed in the blood of high IgG responders, while CD14⁺ and CD16⁺ monocyte populations were decreased in these individuals.</p><p><strong>Conclusion: </strong>These results demonstrate the induction of treatment-specific circulating humoral immunity by a bacterial consortium and suggest potential mechanisms by which gut microbes may contribute to antitumor immunity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692054","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}

{"title":"Inhibition of stromal MAOA leading activation of WNT5A enhance prostate cancer immunotherapy by involving the transition of cancer-associated fibroblasts.","authors":"Zhite Zhao, Yaohua Hu, Hui Li, Tong Lu, Xinglin He, Yifan Ma, Minli Huang, Mengyao Li, Lijun Yang, Changhong Shi","doi":"10.1136/jitc-2024-010555","DOIUrl":"10.1136/jitc-2024-010555","url":null,"abstract":"<p><strong>Background: </strong>The interaction between stromal cells and the tumor immune microenvironment (TIME) is acknowledged as a critical driver in the progression of prostate cancer (PCa). Monoamine oxidase A (MAOA), a mitochondrial enzyme that catalyzes the degradation of monoamine neurotransmitters and dietary amines, has been linked to the promotion of prostate tumorigenesis, particularly when upregulated in stromal cells. However, the detailed mechanisms of MAOA's interaction with TIME have not been fully elucidated.</p><p><strong>Methods: </strong>We reanalyzed a single-cell sequencing dataset to evaluate the role of MAOA in the stroma, verify the impact of stromal MAOA alterations on CD8⁺ T cell responses by co-culturing stromal cells and immune cells in vitro. Furthermore, C57BL/6J mouse subcutaneous transplant tumor models and dual humanized mouse models were established to investigate the function of MAOA in vivo and the potential of its inhibitors for immunotherapy.</p><p><strong>Results: </strong>Our study demonstrates that inhibiting MAOA in stromal cells facilitates the conversion of myofibroblastic cancer-associated fibroblasts (myCAFs), thereby improving the immunosuppressive environment of PCa. The strategic combination of MAOA inhibition with immune checkpoint inhibitors elicits a synergistic antitumor effect. Specifically, MAOA inhibition in stromal cells leads to increased production of WNT5A, which subsequently activates the cytotoxic capacity of CD8⁺ T cells through the Ca²⁺-NFATC1 signaling pathway.</p><p><strong>Conclusions: </strong>Our findings highlight the critical role of MAOA in modulating cancer-associated fibroblasts within the PCa immune microenvironment, presenting a novel therapeutic strategy to augment the efficacy of immunotherapy for PCa.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692094","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":"A SITC vision: adapting clinical trials to accelerate drug development in cancer immunotherapy.","authors":"Thomas U Marron, Jason J Luke, Brianna Hoffner, Jane Perlmutter, Connie Szczepanek, Valsamo Anagnostou, Ann W Silk, Pedro J Romero, Elizabeth Garrett-Mayer, Leisha A Emens","doi":"10.1136/jitc-2024-010760","DOIUrl":"10.1136/jitc-2024-010760","url":null,"abstract":"<p><p>Clinical trials of cancer immunotherapy (IO) were historically based on a drug development paradigm built for chemotherapies. The remarkable clinical activity of programmed cell death protein 1/programmed death ligand 1 blockade, chimeric antigen receptor-T cells, and T cell engagers yielded new insights into how the mechanistic underpinnings of IO are reflected in the clinic. These insights and the sheer number of novel immunotherapies currently in the pipeline have made it clear that our strategies and tools for IO drug development must adapt. Recent innovations like engineered T cells and tumor-infiltrating lymphocytes demonstrate that immune-based treatments may rely on real-time manufacturing programs rather than off-the-shelf drugs. We now recognize adoptively transferred cells as living drugs. Progression criteria have been redefined due to the unique response patterns of IO. Harnessing the power of both biomarkers and the neoadjuvant setting earlier in drug development is of broad interest. The US Food and Drug Association is increasingly impacting the design of trials with respect to dose optimization and clinical endpoints. The use of novel endpoints such as pathologic complete/major response, treatment-free survival, and minimal residual disease is becoming more common. There is growing acceptance of using patient-reported outcomes as trial endpoints to better measure the true clinical benefit and impact of novel IO agents on quality of life. New opportunities created by modern data science and artificial intelligence to inform and accelerate drug development continue to emerge. The importance of streamlining the clinical research ecosystem and enhancing clinical trial access to facilitate the enrollment of diverse patient populations is broadly recognized. Patient advocacy is critical both to drive the science of IO, and to promote patient satisfaction. To capitalize on these opportunities, the Society for Immunotherapy of Cancer (SITC) has established a goal of at least 100 new, unique IO approvals over the next 10 years. Accordingly, SITC has developed initiatives designed to integrate the viewpoints of diverse stakeholders and galvanize the field in further adapting clinical trials to the unique features of IO, moving us closer to our ultimate goal of using IO to cure and prevent cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692131","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":"Depletion of tumor-derived CXCL5 improves T cell infiltration and anti-PD-1 therapy response in an obese model of pancreatic cancer.","authors":"Richard McKinnon Walsh, Joseph Ambrose, Jarrid L Jack, Austin E Eades, Bailey A Bye, Mariana Tannus Ruckert, Fanuel Messaggio, Appolinaire A Olou, Prabhakar Chalise, Dong Pei, Michael N VanSaun","doi":"10.1136/jitc-2024-010057","DOIUrl":"10.1136/jitc-2024-010057","url":null,"abstract":"<p><strong>Background: </strong>CXCR1/2 inhibitors are being implemented with immunotherapies in PDAC clinical trials. CXC-ligands are a family of cytokines responsible for stimulating these receptors; while typically secreted by activated immune cells, fibroblasts, and even adipocytes, they are also secreted by immune-evasive cancer cells. CXC-ligand release is known to occur in response to inflammatory stimuli. Adipose tissue is an endocrine organ and a source of inflammatory signaling peptides. Importantly, adipose-derived cytokines and chemokines are implicated as potential drivers of tumor cell immune evasion; cumulatively, these findings suggest that targeting CXC-ligands may be beneficial in the context of obesity.</p><p><strong>Methods: </strong>RNA-sequencing of human PDAC cell lines was used to assess influences of adipose conditioned media on the cancer cell transcriptome. The adipose-induced secretome of PDAC cells was validated with ELISA for induction of CXCL5 secretion. Human tissue data from CPTAC was used to correlate IL-1β and TNF expression with both CXCL5 mRNA and protein levels. CRISPR-Cas9 was used to knockout CXCL5 from a murine PDAC KPC cell line to assess orthotopic tumor studies in syngeneic, diet-induced obese mice. Flow cytometry and immunohistochemistry were used to compare the immune profiles between tumors with or without CXCL5. Mice-bearing CXCL5 competent or deficient tumors were monitored for differential tumor size in response to anti-PD-1 immune checkpoint blockade therapy.</p><p><strong>Results: </strong>Human adipose tissue conditioned media stimulates CXCL5 secretion from PDAC cells via either IL-1β or TNF; neutralization of both is required to significantly block the release of CXCL5 from tumor cells. Ablation of CXCL5 from tumors promoted an enriched immune phenotype with an unanticipatedly increased number of exhausted CD8 T cells. Application of anti-PD-1 treatment to control tumors failed to alter tumor growth, yet treatment of CXCL5-deficient tumors showed response by significantly diminished tumor mass.</p><p><strong>Conclusions: </strong>In summary, our findings show that both TNF and IL-1β can stimulate CXCL5 release from PDAC cells in vitro, which correlates with expression in patient data. CXCL5 depletion <i>in vivo</i> alone is sufficient to promote T cell infiltration into tumors, increasing efficacy and requiring checkpoint blockade inhibition to alleviate tumor burden.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692138","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":"PLS-α-GalCer: a novel targeted glycolipid therapy for solid tumors.","authors":"Julian Burks, Shweta Tiwary, David M Stevens, Sarah L Skoczen, Ruvanthi N Kularatne, Stephan T Stern, Jay A Berzofsky","doi":"10.1136/jitc-2024-009539","DOIUrl":"10.1136/jitc-2024-009539","url":null,"abstract":"<p><strong>Background: </strong>The prototypical type I natural killer T (NKT) cell agonist, α-galactosylceramide (α-GalCer), has shown only minimal effects against solid tumors in the clinic. The most promising clinical application of α-GalCer currently entails ex vivo priming of patient-derived dendritic cells; however, this technology suffers from cost, logistical concerns, and safety issues. As a parenteral dendritic cell-targeted alternative, we demonstrate that poly(L-lysine succinylated) (PLS)-α-GalCer, a novel scavenger receptor-A1 targeted α-GalCer prodrug has enhanced antitumor activity compared with α-GalCer.</p><p><strong>Methods: </strong>To compare the antitumor activity of PLS-α-GalCer and α-GalCer, we used mouse syngeneic subcutaneous pancreatic and cervical tumor models using Panc02 and TC-1 cells, respectively. Intratumoral immune cell infiltration was evaluated using flow cytometry and immunohistochemistry whole-slide scan analysis. Serum cytokine levels were examined by ELISA and LEGENDplex analysis. Type I NKT cell intracellular interferon-gamma (IFN-γ) levels were determined by flow cytometry. Immunofluorescence was used to test the uptake and processing of PLS-α-GalCer and α-GalCer in antigen-presenting cells (APCs).</p><p><strong>Results: </strong>The scavenger receptor A1 (SR-A1)-mediated targeting of α-GalCer to APCs by PLS-α-GalCer significantly improves the antitumor function against solid tumors compared with α-GalCer. The Panc02 and TC-1 tumor models demonstrated that PLS-α-GalCer increases intratumoral antigen-specific T, NKT and T cells, and increases the M1/M2 macrophage ratio. In the TC-1 tumor model, we demonstrated that PLS-α-GalCer synergizes with an E7 tumor vaccine to significantly suppress tumor growth and increase the survival of mice. Furthermore, the antitumor function of PLS-α-GalCer is dependent on type I NKT cells and requires SR-A1 targeting. In addition, using SR-A1 knockout RAW cells, a murine macrophage cell line, we showed that PLS-α-GalCer uptake and processing in APCs are more efficient compared with α-GalCer. PLS-α-GalCer also induces significantly less serum Th2 and Th17 cytokines while stimulating significantly more IFN-γ for a longer period and increases Th1:Th2 cytokine ratios compared with α-GalCer.</p><p><strong>Conclusions: </strong>PLS-α-GalCer is a promising immunotherapy for the treatment of solid tumors that has superior antitumor activity compared with α-GalCer and could be combined with tumor vaccines and potentially other immunotherapies such as immune checkpoint inhibitors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692056","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":"Osteoarthritis increases the risk of inflammatory arthritis due to immune checkpoint inhibitors associated with tissue-resident memory T cells.","authors":"Matthieu Paiola, Daniel M Portnoy, Luke Yi Hao, Shoiab Bukhari, Robert J Winchester, Brian S Henick, Adam Mor, Yevgeniya Gartshteyn","doi":"10.1136/jitc-2024-010758","DOIUrl":"10.1136/jitc-2024-010758","url":null,"abstract":"<p><strong>Objective: </strong>Immune checkpoint inhibitors (ICIs) have significantly advanced cancer treatment, but they can also lead to immune-related adverse events (irAEs), including inflammatory arthritis. Understanding the risk factors and underlying mechanisms of irAE pathogenesis is crucial for optimal patient management. Increasing evidence suggests that ICI-mediated activation of tissue-resident memory T cells (T_RM) significantly eliminates cancer cells and is associated with irAE-related colitis and dermatitis. However, it remains unknown why the development of these irAEs is restricted to a subset of patients. We hypothesized that osteoarthritis (OA) associated tissue damage and chronic inflammation lead to the recruitment and differentiation of joint T_RM cells, predisposing individuals to ICI-induced arthritis.</p><p><strong>Methods: </strong>Using a comprehensive approach, we compared the prevalence of OA in patients with irAE-arthritis to those with irAE non-arthritis and those without irAEs. Additionally, we used advanced immunophenotyping techniques to characterize T-cell populations in the blood and synovial fluid of patients with OA and irAE-arthritis.</p><p><strong>Results: </strong>Our findings revealed a significantly higher prevalence of OA in patients who developed irAE-arthritis than controls. Furthermore, the multivariable analysis identified OA, body mass index, and smoking as independent risk factors for the development of irAE-arthritis. T_RM cells expressing programmed cell death protein-1 (PD-1) were the predominant synovial T cells in OA joints. These cells were directly targeted by ICIs, resulting in an inflammatory immune response and the transition from OA to irAE-arthritis.</p><p><strong>Conclusion: </strong>This study, the first of its kind, identifies OA as a significant risk factor for irAEarthritis. It reveals a potential mechanism by which ICIs activate PD-1-positive T_RM cells in OA joints, resulting in tissue inflammation and irAE-arthritis. This research could significantly enhance the management and treatment of patients with cancer receiving ICIs.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673926","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":"Thermoresistant flagellin-adjuvanted cancer vaccine combined with photothermal therapy synergizes with anti-PD-1 treatment.","authors":"Jayalakshmi Thiruppathi, Veena Vijayan, Hye Suk Hwang, Yong Jun Bang, Vandara Loeurng, Seol Hee Hong, Aravindkumar Sundaram, In-Kyu Park, Shee Eun Lee, Joon Haeng Rhee","doi":"10.1136/jitc-2024-010272","DOIUrl":"10.1136/jitc-2024-010272","url":null,"abstract":"<p><strong>Background: </strong>Cancer immunotherapy, leveraging the immune system to target and eradicate cancer cells, has transformed cancer treatment paradigms. Immune checkpoint inhibitors (ICIs) are used in a wide array of cancers, but only a limited fraction of patients are responding. Cancer vaccines could elicit antigen-specific immune responses and establish long-term immune memory, preventing recurrence and metastasis. Despite their promising profiles, ICIs and cancer vaccines by themselves are often insufficient to overcome the immunosuppressive tumor microenvironment (TME) and recurrence/metastasis. Addressing these challenges is crucial for improving cancer immunotherapy outcomes.</p><p><strong>Methods: </strong>The targeted liposomal formulation (TLIF), displaying Cyclic RGD (cRGD) peptide on the surface and encapsulating ICG and thermoresistant flagellin (FlaB) inside, was used for photothermal therapy (PTT), which was designed to induce robust immunogenic cell death (ICD) and release tumor antigens (TAs). We employed a mouse breast cancer model amenable to PTT. Utilizing a bilateral DD-Her2/neu tumor implantation model, we evaluated local and abscopal effects of combinatorial approaches employing PTT, FlaB-adjuvanted peptide vaccine (FlaB-Vax), and anti-PD-1 treatment. FlaB-Vax was designed to trigger tumor-associated antigen (TAA)-specific immune responses, which will trigger specific anti-tumor immunity. TLIF-PTT aimed to reduce tumor burden and induce ICD-mediated TA liberation for epitope spreading. Sustained anti-tumor immune memory was assessed by orthotopic rechallenging cured mice with the DD-Her2/neu tumor cells.</p><p><strong>Results: </strong>The combination of TLIF-PTT and FlaB-Vax provided significantly enhanced primary tumor suppression, with strong abscopal effects and long-lasting immune memory. The addition of anti-PD-1 therapy further improved long-term relapse-free survival, highlighting the potential of this combinatorial approach to induce durable antitumor immunity and sustainably prevent cancer recurrence and metastasis.</p><p><strong>Conclusion: </strong>This study demonstrates that the combination of TLIF-PTT and FlaB-Vax synergistically induced synergistic anti-tumor immune responses, which were efficaciously potentiated by anti-PD-1 treatment for recurrence-free long-term survival.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673932","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":"Letter to the editor: safety and efficacy of PD-1 inhibitor (sintilimab) combined with transarterial chemoembolization as the initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria.","authors":"Bi-Cheng Wang","doi":"10.1136/jitc-2025-011909","DOIUrl":"10.1136/jitc-2025-011909","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673921","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":"Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy.","authors":"Sarah Mertlitz, Katarina Riesner, Martina Kalupa, Nora Uhlig, Steffen Cordes, Lydia Verlaat, Mina Jamali, Ningyu Li, Hadeer Mohamed Elsayed Rasheed Mohamed, Lars Bullinger, Stephen Moss, John Greenwood, Jerome Jatzlau, Petra Knaus, Pedro Vallecillo-Garcia, Olaf Penack","doi":"10.1136/jitc-2024-009372","DOIUrl":"10.1136/jitc-2024-009372","url":null,"abstract":"<p><strong>Background: </strong>Previous data indicated that the leucine-rich α-2 glycoprotein 1 (LRG1) pathway contributes to vascular dysfunction during cancer growth. Therapeutic targeting of LRG1 normalized tumor vessel dysfunction and enhanced the efficacy of anti-cancer adoptive T cell therapy. A major clinical problem after allogeneic hematopoietic stem cell transplantation (alloHSCT) and after chimeric antigen receptor (CAR) T-cell therapy is the induction of hyperinflammatory side effects, which are typically associated with severe endothelial dysfunction.</p><p><strong>Methods: </strong>We investigated LRG1 in preclinical models and in patient samples.</p><p><strong>Results: </strong>In prospective studies, we found elevated LRG1 serum levels in patients with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome after CAR-T-cell therapy as well as in patients with acute graft-versus-host disease (aGVHD) after alloHSCT.In preclinical models of aGVHD, we found vasculature-associated LRG1 upregulation as well as LRG1 pathway gene upregulation. The genetic deletion of LRG1 in alloHSCT donors and in alloHSCT recipients led to reduced clinical and histological aGVHD. In line with this, LRG1 deletion led to clinically and histologically reduced disease severity in experimental inflammatory models of colitis (dextran sulfate sodium colitis) and paw edema. LRG1 deletion reduced inflammation-related vascular leakiness, endothelial cell proliferation, and migration.</p><p><strong>Conclusions: </strong>The current data support the hypothesis that LRG1 is an attractive therapeutic target after alloHSCT and after CAR-T cell therapy for cancer because of its role in dysfunctional tumor vessels as well as in inflammatory complications.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673923","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":"Cardiac MRI study of adverse events in patients treated with immune checkpoint inhibitors: a prospective cohort study of cardiac adverse events.","authors":"Agnese Losurdo, Cristina Panico, Chiara Catalano, Simone Serio, Laura Giordano, Lorenzo Monti, Federica Catapano, Stefano Figliozzi, Carla D'Andrea, Angelo Dipasquale, Pasquale Persico, Antonio Di Muzio, Marco Cremonesi, Alessandro Marchese, Maria Chiara Tronconi, Matteo Perrino, Giovanna Finocchiaro, Enrico Lugli, Marco Francone, Armando Santoro, Gianluigi Condorelli, Matteo Simonelli, Marinos Kallikourdis","doi":"10.1136/jitc-2024-010568","DOIUrl":"10.1136/jitc-2024-010568","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) revolutionized cancer therapy, yet require management of immune-related adverse events (irAEs). Fulminant myocarditis is a rare irAE, but lower-severity cardiac events are being reported more frequently, leading to an unmet need for irAE prevention, early diagnosis, and treatment, especially for long-life-expectancy patients. We recruited 57 patients, stratified according to therapy regime (monotherapy (30%) or combination (33%) cohort) or history of cardiac disease or presence of at least two cardiovascular risk factors other than prior or active smoking (cardiovascular cohort (37%)). We performed a complete cardiological assessment with clinical visit, 12-lead ECG, multiparametric cardiac MRI as well as peripheral blood mononuclear cell immunophenotyping, prior to ICI initiation and around 2 months later. ICI treatment was associated with a significant left ventricular ejection function (LVEF) reduction pre-ICI versus post-ICI treatment (60.1±8% to 58.1±8%, p=0.002, paired t-test) and more than 3% LVEF loss in a substantial proportion of patients (18; 32%). These patients also showed significantly higher T2 values (p=0.037, unpaired t-test), putative sign of cardiac edema. The loss of cardiac function did not differ among patients with different tumor types, therapy regimes or history of cardiac disease. Immunophenotyping analyses showed a reduction of programmed cell death protein 1 staining on both CD4⁺ and CD8⁺ T cells, and an upregulation of HLA-DR on CD8⁺ T cells. Using a very sensitive and comprehensive approach in patients unselected for cardiac history, we found a subclinical but significant LVEF decrease. These findings may inform ongoing discussions on optimal management of cardiac irAEs in patients undergoing ICI treatment and warrant further evaluation.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663409","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}