Frontiers in Immunology最新文献

{"title":"Correction: Protection against <i>N. gonorrhoeae</i> induced by OMV-based meningococcal vaccines are associated with cross-species directed humoral and cellular immune responses.","authors":"Weiyan Zhu, Andreea Waltmann, Marguerite B Little, Kristie L Connolly, Kathryn A Matthias, Keena S Thomas, Mary C Gray, Aleksandra E Sikora, Alison K Criss, Margaret C Bash, Andrew N Macintyre, Ann E Jerse, Joseph A Duncan","doi":"10.3389/fimmu.2025.1697855","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1697855","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fimmu.2025.1539795.].</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1697855"},"PeriodicalIF":5.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12464695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A real-time imaging approach to quantify dendritic cell internalization for immunogenicity risk assessment of biotherapeutics.","authors":"Zhaojun Yin, Peter Tran, Joyce Guerrero, Justin Low, Qing Xie, Kun Peng","doi":"10.3389/fimmu.2025.1632302","DOIUrl":"10.3389/fimmu.2025.1632302","url":null,"abstract":"<p><p>The presence of treatment-emergent anti-drug antibodies (ADAs) can pose challenges during biotherapeutic development by compromising drug safety and efficacy. Early assessment of immunogenicity risk is essential to mitigate these risks. Dendritic cells (DCs) are crucial for priming CD4 T cells and necessary for effective antibody production. Therefore, DC internalization has been investigated as a predictive tool for evaluating the immunogenicity risk of biotherapeutics. Previously reported flow cytometry-based DC internalization assays, including our own, have faced several limitations. These limitations included low throughput due to a restricted DC supply from healthy donors, restriction to Fc-containing antibody-based biotherapeutics, and offering only endpoint data. To address these limitations, we explored both direct and indirect labeling approaches using the IncuCyte® real-time imaging platform. Our findings revealed that indirect labeling approach with the commonly used Fab anti-Fc reagents was unsuitable for DC internalization assays due to significant assay background noises and assay bias when evaluating biotherapeutics of different frameworks. In contrast, using direct labeling with Biotracker Orange demonstrated improved predictability, required fewer DCs, and was suitable for high-throughput screening. Additionally, this approach facilitates constant monitoring of the internalization process, offering a comprehensive understanding of cell morphology changes and internalization kinetics. Using a panel of 25 test therapeutic antibodies with known clinical ADA results, the IncuCyte®-based direct labeling assay demonstrated significant improvements in predicting the immunogenicity risk of the tested molecules. The assay demonstrated a high correlation between internalization and clinical immunogenicity risk, outperforming our previous flow cytometry-based results. Overall, the IncuCyte®-based direct labeling assay using Biotracker Orange represents a significant advancement compared to our previous flow cytometry assay. This new technique is a valuable addition to our immunogenicity risk assessment toolbox, and will ultimately lead to more informed decision-making in the early development of biotherapeutics.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1632302"},"PeriodicalIF":5.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12463596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case Report: Psychogenic purpura in a uremic patient on peritoneal dialysis.","authors":"Lin Zhang, Hanqing Zhang, Yuetong Zhao, Tao Zhang, Zhengjie Zhu, Yanheng Qiao, Yongming Tian, Hang Su, Jie Li, Bo Yang","doi":"10.3389/fimmu.2025.1625126","DOIUrl":"10.3389/fimmu.2025.1625126","url":null,"abstract":"<p><p>Psychogenic purpura (Gardner-Diamond syndrome) is a rare autoimmune vasculopathy characterized by the spontaneous onset of painful edema and infiltrative cutaneous lesions that rapidly develop into ecchymosis after severe psychological stress events. In this article, we report an 87-year-old female uremic patient who was admitted to the hospital with erythema and subcutaneous ecchymoses on the head and face following an Aedes mosquito sting. She was previously diagnosed with \"toxic insect stings and skin bacterial infections\" and was given anti-infective treatment by an outside hospital, which was ineffective. Subsequent laboratory tests at our hospital revealed only an increase in fibrinogen and leukocytosis. Tracing the history revealed that the patient's purpura episodes were related to a major life event, the death of her husband. After consultation with the dermatology department, the patient's autoerythrocyte sensitization test was positive, and she was finally diagnosed with \"psychogenic purpura\". Treatment included glucocorticoids and immunomodulators, supplemented by anti-infective and renal replacement therapy, and the patient's ecchymosis gradually subsided and resolved after one month of follow-up. This case highlights the complexity of diagnosing psychogenic purpura and the significance of medical history in the diagnosis. Only accurate and timely diagnosis can effectively avoid unnecessary treatment.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1625126"},"PeriodicalIF":5.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12463969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Air pollution-related immune gene prognostic signature for hepatocellular carcinoma: network toxicology, machine learning and multi-omics analysis.","authors":"Lei Pu, Xiaoyan Zhang, Cheng Pu, Peng Sun","doi":"10.3389/fimmu.2025.1638445","DOIUrl":"10.3389/fimmu.2025.1638445","url":null,"abstract":"<p><strong>Background: </strong>Air pollution may crosstalk with immune system to promote hepatocellular carcinoma (HCC) development, but its precise mechanisms and prognostic significance remain unclear.</p><p><strong>Objective: </strong>This study aims to construct a prognostic signature for HCC based on air pollutant-related immune genes (APIGs).</p><p><strong>Methods: </strong>We obtained mRNA-seq and scRNA of HCC from GEO, TCGA and ICGC. AP-related target genes were retrieved from several online databases. APIGs were obtained using WGCNA, differential gene expression analysis and immune infiltration analysis. Molecular subtypes were conducted based on APIG expression to characterize immune features. A total of 101 combinations of 10 machine learning algorithms were used to construct an APIG-based prognostic signature (APIGPS). Furthermore, we performed qRT-PCR, survival analyses, functional enrichment, immune infiltration and single-cell analyses. Subsequently, LASSO, RF, and RFE-SVM were employed to identify diagnostic genes, followed by pan-cancer analysis.</p><p><strong>Results: </strong>We identified 19 APIGs. HCC samples were divided into 3 subtypes, with C1 exhibiting a pro-tumor immune microenvironment and poorer prognosis. APIGPS constructed by 7 APIGs (CDC25C, MELK, ATG4B, SLC2A1, CDC25B, APEX1, GLS), demonstrated robust predictive ability independent of clinical features. The biological pathway differences between APIGPS-based high- and low-risk groups involved immune responses and cell proliferation and migration. APIGPS genes had stable binding to 7 APs and were mainly expressed in macrophages, with HRG exhibiting higher macrophage abundance. CDC25C was identified as the hub gene after intersecting diagnostic genes and APIGPS genes. CDC25C was associated with survival of 10 cancers, MSI in 10 cancers, TMB in 21 cancers, and immune cell abundance in 13 cancers.</p><p><strong>Conclusions: </strong>We identified key APIGs and constructed a robust APIG-based prognostic signature for HCC. CDC25C was a key target through which APs impact HCC and multiple other cancers.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1638445"},"PeriodicalIF":5.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12463942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dexamethasone induced Dectin-1 activation enhances NLRP3 inflammasome activation.","authors":"Ruth-Miriam Koerber, Sebastian Oberbeck, Philipp Kotthoff, Solveig N Daecke, Peter Brossart, Stefanie A E Held","doi":"10.3389/fimmu.2025.1656288","DOIUrl":"10.3389/fimmu.2025.1656288","url":null,"abstract":"<p><p>Systemic candidiasis is a serious complication in immunocompromised patients, with Candida albicans emerging as the most common opportunistic pathogen. In various therapeutic treatment regimens the immunosuppressive agent Dexamethasone is used. Dexamethasone itself impairs the function of dendritic cells and reduces thereby their capacity for T-cell proliferation through the activation of Dectin-1 by β-glucans. In the present study, we reveal that these tolerogenic dendritic cells (Dex-DCs) have an increased secretion of IL-1ß and IL-18 when stimulated with β-glucans. We show an increased formation of ASC specks, which are crucial for recruiting pro-caspase-1, indicating an elevated inflammasomal activity. In line with this, we were able to show that treatment of tolerogenic dendritic cells with a NLRP3 inhibitor prior to Dectin-1 stimulation normalized the secretion of IL-1ß and IL-18. Furthermore, the addition of Caspase- and Syk-inhibitors led to diminished inflammasome activation as well as to less pyroptosis and apoptosis in response to β -glucan stimulation. Finally, we identified elevated production of reactive oxygen species (ROS) upon β-glucan stimulation in DexDCs as a possible mechanism for apoptosis induction as it can be reversed by the treatment with a specific anti-Dectin-1 antibody. Moreover, the underlying mechanism of the NLRP3 activation seems to be mediated through mitochondrial DNA release induced by mitochondrial ROS. Taken together, the present study demonstrates that Dectin-1 stimulation of tolerogenic DCs can result in severe pro-inflammatory responses due to cytokine release and subsequent NLRP3 inflammasome activation. In conclusion, the application of NLRP3 inflammasome inhibitors to patients treated with corticosteroids like Dexamethasone may significantly improve their outcome as they might be well-protected against local or severe systemic fungal infections.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1656288"},"PeriodicalIF":5.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunomodulatory peptide-drug conjugate MEL-dKLA suppresses progression of prostate cancer by eliminating M2-like tumor-associated macrophages.","authors":"Ik-Hwan Han, Ilseob Choi, Soyoung Kim, Minjin Kwon, Hyojung Choi, Hyunsu Bae","doi":"10.3389/fimmu.2025.1652166","DOIUrl":"10.3389/fimmu.2025.1652166","url":null,"abstract":"<p><p>Prostate cancer is one of the most common malignancies in men and is frequently associated with tumor-promoting inflammation. Tumor-associated macrophages (TAMs) are known to facilitate cancer progression by suppressing antitumor immunity. Therefore, targeting TAMs represents a promising strategy for cancer therapy. This study aimed to investigate whether melittin-dKLA, a conjugated peptide consisting of melittin (MEL), which selectively binds M2-like macrophages, and the pro-apoptotic peptide d(KLAKLAK)₂ (dKLA), can inhibit prostate cancer progression by targeting M2 macrophages. Human monocytic cells (THP-1 cells) were differentiated into TAMs using tumor-conditioned medium (TCM), and the conditioned medium from these TAMs was termed M-TCM. MEL-dKLA binding affinity was assessed using FITC-labeled melittin. A prostate cancer mouse model was established by subcutaneous injection of TRAMP-C2 cells, followed by MEL-dKLA administration every three days. As a result, THP-1-derived macrophages stimulated with TCM exhibited elevated expression of M2 markers (ARG1, CD206, and CD163). Prostate cancer cells (PC-3) stimulated with M-TCM showed increased proliferation and expression of epithelial-mesenchymal transition (EMT) markers. MEL-dKLA preferentially bound to M2 macrophages and TAMs, and inducing selective cytotoxicity. Conditioned media from MEL-dKLA-treated M2 macrophages and TAMs resulted in markedly decreased PC-3 cell proliferation, migration, and invasion. <i>In vivo</i>, MEL-dKLA treatment significantly reduced tumor growth, decreased the number of CD163⁺ M2 macrophages, and increased CD8⁺ T cell infiltration in tumor tissues. These findings demonstrate that MEL-dKLA suppresses prostate cancer progression by targeting M2-like TAMs both <i>in vitro</i> and <i>in vivo</i>. MEL-dKLA may serve as a promising therapeutic agent to modulate the tumor microenvironment in prostate cancer.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1652166"},"PeriodicalIF":5.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12463987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Tick cysteine protease inhibitors suppress immune responses in mannan-induced psoriasis-like inflammation.","authors":"Huimei Wu, Mohamed Amine Jmel, Jinwei Chai, Maolin Tian, Xueqing Xu, Yuan Hui, Kutty Selva Nandakumar, Michail Kotsyfakis","doi":"10.3389/fimmu.2025.1699570","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1699570","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fimmu.2024.1344878.].</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1699570"},"PeriodicalIF":5.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term survival benefit from third-line treatment for advanced colon cancer: a case report.","authors":"Ju Su, Yuqing Kuang, Yiwen Wu, Qun Chen, Shadong Min","doi":"10.3389/fimmu.2025.1639287","DOIUrl":"10.3389/fimmu.2025.1639287","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is a common malignancy with a relatively high incidence and mortality rate. Treatment options for metastatic CRC (mCRC) in the third-line setting remain limited. This article reports a case of colon cancer with liver metastases that progressed after comprehensive treatment but achieved a prolonged progression-free survival of over 38 months with third-line immunotherapy combined with targeted therapy. This aim is to improve understanding of CRC with liver metastasis and provide a clinical reference for managing similar cases.</p><p><strong>Case presentation: </strong>A 69-year-old male presented to the People's Hospital of Xiangxi Autonomous Prefecture in April 2021 with a 2-week history of fatigue and abdominal distension. His medical history included type 2 diabetes mellitus and diabetic peripheral neuropathy, managed with long-term insulin therapy. Based on clinical presentation, imaging studies, gastroscopy and colonoscopy, and pathological findings, he was diagnosed with moderately to poorly differentiated adenocarcinoma of the ascending colon with liver metastasis (cT4aN0M1a IVA, proficient mismatch repair [pMMR], clinical risk score [CRS] 2). The patient received 6 cycles of neoadjuvant chemotherapy with oxaliplatin, calcium folinate, and fluorouracil (the first 3 cycles combined with bevacizumab), followed by radical resection of the primary tumor and resection of complex liver metastases. Postoperatively, he underwent five cycles of adjuvant chemotherapy with oxaliplatin, calcium folinate, and fluorouracil (the last four cycles combined with bevacizumab). In November 2021, bilateral lung metastases were detected. The patient then received three cycles of chemotherapy with fluorouracil, calcium folinate, and irinotecan, but the disease continued to progress. From February 2022 to April 2025, third-line treatment with fruquintinib (targeted therapy) combined with sintilimab (immunotherapy) was initiated.</p><p><strong>Conclusion: </strong>Fruquintinib combined with sintilimab immunotherapy may represent a promising third-line treatment option for patients with pMMR mCRC.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1639287"},"PeriodicalIF":5.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12463852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal evaluation of T-cell responses to Pfizer-BioNTech and Janssen SARS-CoV-2 vaccines as boosters in Ghanaian adults.","authors":"Frank Osei, Kekeli Korshi Tudzi, Isaac Otieno Othol, Selorm Philip Segbefia, Diana Ahu Prah, Evans Nii Armah-Vedjesu, Abigail Naa Adjorkor Pobee, Oscar Nii Otto Darko, Theophilus Brenko, Doreen Teye-Adjei, Stella Nartey, Jones Amo Amponsah, Vincent Amarh, Godfred Futagbi, Dorcas Obiri-Yeboah, Frederica Dedo Partey, Michael Fokuo Ofori, Kwadwo Asamoah Kusi","doi":"10.3389/fimmu.2025.1643083","DOIUrl":"10.3389/fimmu.2025.1643083","url":null,"abstract":"<p><strong>Introduction: </strong>In Ghana, at least five different COVID-19 vaccines based on mRNA or adenovirus vector delivery platforms have been authorized by the Ghana Health Service for vaccination. Although these vaccines have been instrumental in the control of COVID-19, data on the longevity of induced immunity in vaccinated individuals in Ghana is limited. This study aimed at assessing the cellular immune response kinetics among Ghanaians receiving booster vaccinations with the mRNA-based Pfizer and adenovirus-based Janssen COVID-19 vaccines.</p><p><strong>Methods: </strong>We conducted a longitudinal study using 48 Ghanaian adults who had completed primary vaccination series and administered a booster shot with either of the two vaccines. Pre-booster blood samples were collected to serve as the baseline, and post-booster samples at months 3, 6, and 9 for immunological analysis. T-cell responses were assessed using Luminex multiplex assay following stimulation of Peripheral Blood Mononuclear Cells (PBMCs) from study participants with SARS-CoV-2 antigens, whereas immune checkpoint molecules expression was assessed by flow cytometry.</p><p><strong>Results: </strong>Appreciable levels of the Th1 cytokines IL-1β, IL-6, IFN-γ and TNF-α and low levels of IL-2, IL-12 and IL-17A were observed in both groups. The Janssen vaccine booster elicited a more sustained cellular response over the nine months, while the Pfizer vaccine booster group showed signs of response decline after three months. Further sub-analysis showed that persons who received an mRNA-based primary vaccination before a viral vector vaccine booster had more durable cytokine responses. Checkpoint molecules, PD-1, CTLA-4 and TIM-3 were expressed at low levels (<10% of CD4+ or CD8+ T cell population with p-values > 0.05) and comparable between the two groups over the nine months.</p><p><strong>Discussion/conclusions: </strong>Levels of some cytokines were generally more sustained in the Janssen group compared to the Pfizer group. Heterologous vaccine recipients exhibited more efficient cellular immune responses compared to homologous recipients. In addition, T-cell inhibitory molecule kinetics suggests an efficient T-cell activity. These findings may have implications for the overall induction of long-term protective immunity by the two vaccine types.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1643083"},"PeriodicalIF":5.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12463971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low rather than high interleukin-6 levels are associated with immune-related adverse events in cancer patients treated with immune checkpoint inhibitors.","authors":"Iñigo Les, David de Haedo, Mireia Martínez, Berta Ibáñez-Beroiz, Amaia Moreno, Ibone de Elejoste, Ana Campillo-Calatayud, Inés Pérez-Francisco, María Cabero, Iñaki Elejalde, Virginia Arrazubi","doi":"10.3389/fimmu.2025.1677778","DOIUrl":"10.3389/fimmu.2025.1677778","url":null,"abstract":"<p><strong>Background: </strong>Among the biomarkers associated with immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) in cancer patients, interleukin-6 (IL-6) has emerged as a key predictive factor. However, it remains unclear whether high or low levels of IL-6 predispose patients to irAEs. Our objective was to evaluate the strength of the association between circulating IL-6 levels, measured in cancer patients before and after initiating ICIs, and the risk of irAEs.</p><p><strong>Methods: </strong>In this multicenter, prospective pan-cancer cohort study, serum IL-6 levels were quantified immediately before the first (pre-ICI) and second (post-ICI) cycles of ICI therapy. To assess the association between IL-6 and irAEs, Fine and Gray competing risk regression models were fitted, considering irAEs as the main event and death as the competing event. The incremental predictive value of IL-6 levels was evaluated using Harrell's C-index.</p><p><strong>Results: </strong>Overall, 224 patients were followed up for a median of 75.5 days after ICI initiation. The adjusted 1-year cumulative incidence of irAEs was 49.0% (95% confidence interval [95%CI], 41.9-55.6%). Multivariate regression models identified female sex (hazard ratio [HR], 1.81; 95%CI, 1.17-2.81; p=0.008), dual ICI therapy with nivolumab plus ipilimumab (HR, 1.86; 95%CI, 1.14-3.02; p=0.012) and post-ICI IL-6 levels (HR, 0.97; 95%CI, 0.94-1.00; p=0.049) as independent risk factors for irAEs. Using standardized post-ICI IL-6 levels, the effect was stronger, with an HR of 0.74 (95% CI, 0.55-1.00; p=0.049). Adding post-ICI IL-6 levels to a model containing established irAE risk factors improved the Harrell's C-index from 0.623 to 0.640.</p><p><strong>Conclusion: </strong>In cancer patients treated with ICIs, low rather than high post-ICI IL-6 levels, female sex and dual ICI therapy are independent risk factors for irAEs.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1677778"},"PeriodicalIF":5.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12464006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}