Journal of Immunotherapy最新文献

Acylation modification plays a crucial role in modulating head and neck squamous cell carcinoma (HNSCC) progression, and their specific prognostic implications in HNSCC have not been thoroughly investigated. Eleven acylation modifications (AM) (crotonylation, lactylation, succinylation, benzoylation, butyrylation, malonylation, glutarylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, palmitoylation, myristoylation, and prenylation) were generated consensus cluster. Then, WGCNA was utilized to identify module genes. Finally, a machine learning approach was used to create AM.score. This analysis revealed 2 distinct subtypes of AMs, each characterized by unique molecular signatures. By integrating different categories of genes, including DEGs, module genes, and AM-related genes, 16 hub genes were identified, and an AM.score was developed. AM.score was rigorously validated across independent external cohorts (TCGA-HNSCC, GSE41613, GSE42743, and GSE65858) and an in-house cohort, demonstrating its reliability and potential applicability. The AM.score serves a dual purpose in its application, as it encapsulates the essential clinical context and offers valuable insights regarding the efficacy of immunotherapy treatments. In particular, patients categorized with a high AM.score displayed a TME that was more actively engaged, which corresponded with a poor prognosis. Furthermore, these patients demonstrated a high level of responsiveness to immunotherapy interventions. Furthermore, an examination using scRNA-seq indicated that patients with high AM.score exhibited heightened cell proliferation and malignancy. This novel AM.score could effectively assess the prognosis and therapeutic responses of HNSCC patients, providing new perspectives for individualized treatment for the patient population.

Immunotherapy with immune checkpoint inhibitors (ICI) is widely used to treat cancers, and reports of rare immune-related adverse events (irAEs) are increasing. Ear, nose, and throat (ENT) irAEs are often underestimated, as patients rarely report rhinorrhea and most cases of sinusitis are asymptomatic, detected only during tumor CT assessments. We report a rare case of severe rhinosinusitis with hearing loss after ipilimumab and nivolumab combination therapy for melanoma. Due to steroid dependency, the patient was successfully treated with intravenous infliximab but was left with residual deafness. Physicians should be aware of these potentially serious ENT complications, which can affect quality of life, to allow timely referral to an ENT specialist. In severe cases, multidisciplinary care is needed to consider steroid-sparing treatments such as infliximab.

Summary: Ubiquitin-proteasome system (UPS) is implicated in pathogenesis and progression of esophageal squamous cell carcinoma (ESCC), representing a promising therapeutic target. However, clinical significance of UPS in ESCC remains incompletely elucidated. UPS genes associated with ESCC survival were first screened through univariate Cox regression analysis. Consensus clustering was performed on TCGA-ESCC cohort based on these genes. Functional enrichment, tumor immune microenvironment analysis, and somatic mutation profiling were conducted for different clusters. Potential therapeutics and biomarkers were evaluated, and miRNA-TF-hub gene regulatory network was constructed. ESCC samples were stratified into 2 distinct clusters (cluster 1 and cluster 2), with cluster 1 demonstrating superior overall survival. Differential analysis revealed enrichment in cell adhesion and calcium signaling pathways. Immune infiltration analysis indicated elevated CD8+ T cells, mast cells, neutrophils, and TILs in cluster 2, alongside lower TIDE scores. TP53 exhibited the highest mutation frequency (93% vs. 86% in cluster 1 vs. cluster 2). Selumetinib, entinostat, and erlotinib were identified as candidate drugs for cluster 2, whereas tozasertib, alpelisib, and cediranib showed higher suitability for cluster 1. Ten potential biomarkers, 13 transcription factors, and 2 miRNAs were characterized. This study elucidates the role of UPS in ESCC progression and provides a framework for personalized treatment strategies.

Disulfidptosis is a newly defined disulfide stress-induced cell death. However, there are gaps in the prognostic role of disulfidptosis-related genes (DRGs) and their correlation with the tumor microenvironment (TME) in gastric cancer (GC). In here, we systematically investigated DRG changes at genomic and transcriptional levels, prognostic value, and their expression patterns in GC. Fifteen DRGs were used to identify the different subtypes, and the differences in prognosis and immune infiltration among the subtypes were examined. We identified 3 distinct molecular subtypes and observed profound differences among the 3 subtypes in clinical outcomes and infiltrating immune cells. Subsequently, a disulfidptosis-related signature (DRG_score) was constructed based on the overlapped disulfidptosis phenotype-related differentially expressed genes and was verified in an external cohort. The multivariate analysis confirmed that the DRG_score serves as an independent prognostic indicator for GC, and then a nomogram was built to increase the clinical applicability of the DRG_score. Furthermore, significant variations were observed in the TME, expression of multiple immune checkpoints, microsatellite status, tumor mutational burden, and response to different chemotherapeutics among the 2 DRG_score groups. A low DRG_score implies more significant TME cell infiltration and better response to immunotherapy. In conclusion, we present a comprehensive overview of the DRG profile in GC and develop a novel signature for GC patients. These findings could help us better understand DRG in GC and provide a theoretical foundation for future studies targeting disulfidptosis in GC.

Summary: Although targeting programmed cell death ligand 1 (PD-L1) has been ineffective in reducing pancreatic ductal adenocarcinoma (PDAC) burden in preclinical and clinical studies, it is unknown if increasing activated CD8+ T-cell numbers, independently or in combination with anti-PD-L1 therapeutics, would improve tumor response. To facilitate evaluation of novel combinatorial strategies targeting PDAC, this study developed a modeling framework to assess therapies targeting PD-L1 and T-cell activation. Chitosan nanoparticles (CNP) loaded with a model antigen have recently shown promising anti-tumor effects by increasing dendritic cell (DC) mediated T-cell activation in a murine PDAC model. Using these in vivo data, along with in vitro and primary and liver metastatic PDAC in situ data, a 3D continuum mixture model of PDAC was rigorously calibrated and solved through distributed computing. The model was applied to analyze the response to anti-PD-L1 and/or antigen-CNP therapies at primary and liver metastatic sites. The results show realistic evaluation of combination therapy targeting PDAC at primary and liver metastatic sites. With the given parameter set, the model projects that anti-PD-L1 therapy and antigen-CNP would synergistically decrease tumor burden at primary and liver metastatic sites to 53.2% and 58.4% of initial burden 5.0 and 5.2 days post-treatment initiation, respectively. Delaying antigen-CNP application 3 or 5 days after anti-PD-L1 and gemcitabine administration further limited metastatic PDAC to <50% of initial burden 15 days post-treatment initiation. In conclusion, the proposed modeling approach enables realistic evaluation of novel combinations of agents, with the goal to design improved PDAC therapy.

This multicenter retrospective study assessed the safety and antitumor activity of cadonilimab in patients with recurrent or metastatic cervical cancer, particularly those with negative PD-L1 expression. Patients received cadonilimab, with or without additional treatments like chemotherapy, bevacizumab, or radiotherapy, and were monitored every 3 weeks until disease progression or intolerable toxicity was observed. The study included 21 patients: 18 with recurrent/metastatic cervical cancer (Figo IB1-IIIC) and 3 with newly diagnosed advanced cervical cancer (Fig IVB). The median follow-up duration was 9.7 (IQR: 2.3-23.6) months, and the median number of treatment cycles for cadonilimab was 10. Six patients had PD-L1-positive expression, and 6 had PD-L1-negative expression. Two patients with newly diagnosed advanced cervical cancer and 3 with recurrent disease achieved complete response; 10 patients had a partial response, and 1 patient had stable disease. Objective response rates were 71.4% (15 of 21 patients) overall and 66.7% (4 of 6 patients) for patients with PD-L1-negative expression. Grade 3-4 treatment-related adverse events occurred in 33.3% of patients, while immune-related adverse events were all G1-2 and occurred in 2 (9.5%) patients. No patients discontinued treatment due to intolerable toxicities. The study concluded that cadonilimab-containing therapies showed promising results in terms of responses and survival outcomes, with a favorable safety profile.

Cancer-related fibroblasts (CAFs), crucial in the tumor microenvironment, significantly influence tumorigenesis and extracellular matrix shaping. This study aimed to analyze the expression of CAF marker genes in lung adenocarcinoma (LUAD) and create a prognostic signature. We included 716 LUAD patients from different cohorts, conducting a comprehensive analysis of single-cell RNA sequencing data from the Gene Expression Omnibus (GEO) database, identifying 227 CAF marker genes. Using the Cancer Genome Atlas (TCGA) LUAD cohort, we developed a 3-gene prognostic signature, categorizing patients into high-risk and low-risk groups. The signature's predictive capability was validated across clinical subgroups and GEO cohorts. It was determined as an independent prognostic factor via univariate and multivariate analyses, leading to the construction of a nomogram for clinical prognosis prediction. Immune profile analysis indicated that high-risk patients exhibited immunosuppression and immune cell infiltration, while the tumor immune dysfunction and exclusion score suggested higher immunotherapy sensitivity in the low-risk group. In addition, high-risk patients showed greater sensitivity to several first-line chemotherapeutic drugs. The expression of hub genes was validated using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and the Human Protein Atlas (HPA). In conclusion, this study presented a novel prognostic signature for LUAD patients based on CAF marker genes, demonstrating strong predictive power for prognosis and treatment response.

Summary: To investigate the clinical characteristics of isolated adrenocorticotropic hormone deficiency (IAD) induced by pembrolizumab, and to provide reference for diagnosis and treatment. Clinical reports of pembrolizumab-induced IAD before February 28, 2025 were collected for retrospective analysis. Twenty (51.3%) women and 19 (48.7%) men entered the study, with a median age of 66 years (range: 38-85). The median time for the onset of IAD was 7.3 months (range: 2-30) after initial administration, and the median cycle was 7 cycles (range: 2-40). Fatigue (65.8%) and anorexia (52.6%) were the most common complaints. Hyponatremia (92.3%) and eosinophilia (33.3%) were the laboratory abnormalities most commonly associated with IAD. Pituitary magnetic resonance imaging (MRI) was normal in most patients (88.2%). After receiving glucocorticoid therapy, patients' symptoms improved significantly with or without pembrolizumab. Pembrolizumab-induced IAD is a rare disease that needs to be paid sufficient attention to. IAD patients have nonspecific manifestations and may be delayed in diagnosis. Further studies are needed to confirm the risk factors and prognosis of pembrolizumab-induced IAD.

Summary: The lack of targetable mutations in 50% of NSCLC cases and resistance to therapies underscore the need for alternative treatments, with epigenetic strategies potentially regulating tumor suppressor genes to inhibit growth. Our focus is to understand the STAT1-mediated epigenetic and epitranscriptomic modulations, such as R-loop formation, histone methylation/demethylation, histone acetylation and deacetylation, DNA methylation, and m6A RNA methylation, in T helper cell (TH) differentiation to evoke tumor-protective immune responses in non-small cell lung cancer (NSCLC) by knocking out (KO) and overexpressing (OE) STAT1. Peripheral blood mononuclear cells (PBMCs) were isolated from NSCLC patients and healthy controls using Ficoll-Hypaque density-gradient centrifugation. CD4+ T cells were purified with magnetic activated cell sorting (MACS). Subsequently, CRISPR/Cas9 knock-out and overexpression techniques were applied, followed by qRT-PCR to evaluate 5-mC, m6A RNA methylation, gene expression, and transcription factor enrichment. Mutations in STAT1 can cause severe immunodeficiency and malignancy, linked to genomic instability from R-loops-DNA-RNA hybrids that lead to DNA breaks through transcription-coupled nucleotide excision repair. Our study examines epigenetic regulators in CD4+ T helper cells from NSCLC patients, focusing on the effects of STAT1 depletion and overexpression on R-loop formation at key gene loci specific to T helper cells. Depletion of STAT1 increased R-loop frequencies, DNA methylation, histone deacetylation, and histone methylation, whereas its overexpression decreased them. Abnormal epitranscriptomic alterations, including m6A RNA methylation, were observed, indicating that STAT1 is crucial for T helper cell differentiation and immune responses in NSCLC, presenting promising avenues for targeted therapeutic interventions.

Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy across various cancers but can cause immune-related adverse events (irAEs). While common irAEs such as dermatitis, pneumonitis, and colitis are well-documented, rare events like cystitis and ureteritis remain underrecognized. We report 3 cases of ICI-induced cystitis and ureteritis. The first case involves a 67-year-old female with lung cancer who developed immune-related cystitis and ureteritis after 3 cycles of pembrolizumab, with recurrence 8 months after discontinuation. Both episodes presented with hematuria, urinary frequency, and dysuria, and were responsive to corticosteroid treatment. The second case involves a 37-year-old female with cervical cancer who developed a truncal rash, hematuria, urinary frequency, and dysuria after the first cycle of cadonilimab, a PD-1/CTLA-4 bispecific antibody. Her condition worsened with rising serum creatinine levels. Imaging revealed bladder wall thickening and ureteral dilation. Partial symptom relief followed oral corticosteroids, but complete resolution was achieved with intravesical corticosteroid irrigation. The third case describes a 35-year-old female with endometrial cancer who presented with similar urinary symptoms and flank pain after 4 cycles of pembrolizumab. Rapid creatinine elevation necessitated ureteral stent placement, which failed to alleviate symptoms. After exclusion of infectious etiologies, immune-related cystitis/ureteritis was diagnosed. Symptoms resolved with intravenous corticosteroids. This report underscores the importance of early recognition and management of rare urinary irAEs to avoid unnecessary interventions and prolonged interruption of anti-tumor therapy. It also highlights intravesical methylprednisolone as a potential treatment modality that warrants further investigation.