Journal of Immunotherapy最新文献

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.

Adenylate uridylate-rich element genes (AREGs) are crucial in modulating gene expression following transcription. However, the comprehensive role of AREGs in lung squamous carcinoma (LUSC) remains inadequately understood. Transcriptome data from TCGA and GTEx databases to identify differentially expressed AREGs. Clustering algorithms were used to identify AREGs-related subtypes, and a prognostic model was developed through univariate/multivariate and LASSO regression analyses. Following this, we created a nomogram integrating clinical pathologic characteristics and the risk model. The immune microenvironment was evaluated using CIBERSORT, ESTIMATE, and MCPcounter analyses. We examined the mRNA expression of the signature genes in normal and lung squamous carcinoma cells using RT-qPCR. Finally, we assessed the sensitivity to drugs based on the signature genes in risk patients. Patients with the 2 identified molecular subtypes exhibit distinct prognoses and immune microenvironments. We identified 5 genes with prognostic significance that can serve as independent predictors in clinical practice. The low-risk patients demonstrates more favorable prognostic outcomes, while the high-risk patients show elevated immune scores and increased immune cell infiltration, suggesting a favorable response to immunotherapy. RT-qPCR results showed upregulation of FAM83A and TINAGL1 and downregulation of FGG and ADH1C in LUSC. In addition, the low-risk patients show increased sensitivity to vinorelbine. The molecular subtypes and prognostic model based on AREGs demonstrate reliable clinical prognostic value. This finding may contribute to personalized and precise treatment for patients with LUSC, offering new insights for improving patient outcomes.

We present a rare case of aortitis in a 65-year-old male diagnosed with p16-positive, metastatic oropharyngeal squamous cell carcinoma on pembrolizumab therapy. The patient has a history of rheumatoid arthritis. Patient presented to the emergency room with cough, sudden onset pleuritic chest pain, and low-grade fever. Extensive infectious and rheumatological work up for the patient's symptoms yielded no significant findings. Radiologic workup suggested aortic inflammation. Because of the temporal relationship of onset of symptoms with immune checkpoint inhibitor therapy, a diagnosis of immune checkpoint related adverse effect (IrAE) associated vasculitis was established. To our knowledge, this is the first case of this unusual side effect of pembrolizumab presenting in the unique context of underlying autoimmune disease.

Metformin has the potential to synergistically enhance the effect of immune checkpoint inhibitors (ICI) in nonsmall cell lung cancer (NSCLC). We evaluated the association between metformin use before ICI initiation and cancer-specific and all-cause mortality among NSCLC patients. We conducted a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2013-2019), including NSCLC patients with type 2 diabetes who newly initiated ICI therapy and had prior antidiabetic medication use. The exposure was metformin monotherapy versus sulfonylurea and/or dipeptidyl peptidase-4 (DPP-4) inhibitors. The primary outcome was cancer-specific mortality, and the secondary outcome was all-cause mortality. We used stabilized inverse probability of treatment weighting (sIPTW) to adjust for confounders. Fine-Gray competing risk model estimated cancer-specific mortality, while Cox proportional hazards model evaluated all-cause mortality. We included 1123 metformin users and 362 sulfonylurea/DPP-4 users. Although baseline characteristics differed, groups were well balanced after weighting. The adjusted incidence rate (aIR) of cancer-specific mortality was 82 versus 81 (aIR difference=1, 95% CI: -13 to 16), and all-cause mortality was 71 versus 67 (aIR difference=4, 95% CI: -6 to 15) per 100 person-years for metformin and sulfonylurea/DPP-4 users, respectively. Metformin use was not significantly associated with cancer-specific mortality (adjusted hazard ratio (aHR)=1.08, 95% CI: 0.88-1.33) and all-cause mortality (aHR=1.07, 95% CI: 0.90-1.26). In this large, diverse cohort of individuals with NSCLC using ICI, there was no statistically significant association between metformin use and cancer-specific or all-cause mortality.