Patients with autoimmune diseases (AIDs) are at an increased risk of developing cancer; however, the immunometabolic programs that shape this comorbidity remain incompletely defined. We integrated targeted serum metabolomics with multiplex profiling of cytokines, chemokines, and immune checkpoint proteins in patients with five major AIDs-idiopathic inflammatory myopathies, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, and systemic sclerosis-with or without cancer. A total of 49 patients with AID and comorbid cancer (AID-CA), 47 patients with AID alone, and 15 healthy controls were enrolled. Compared with AID alone, AID-CA was associated with coordinated remodeling of amino acid and nucleotide metabolism, dominated by the alanine, aspartate, and glutamate pathways. Decreased L-glutamine and increased L-glutamic acid levels were consistently observed and remained significant after the false discovery rate correction. Immune profiling revealed modest but consistent differences, including higher levels of CXCL9 and Galectin-9 and lower levels of selected checkpoint molecules in AID-CA. The effects of major metabolites and immune mediators were directionally stable after adjusting for age, sex, treatment exposure, and autoimmune disease subtype. Integrative analyses revealed stronger associations between metabolites and immune mediators in AID-CA, centered on CXCL9 and Galectin-9, and linked to amino acid and pyrimidine metabolism. In ex vivo assays, perturbation of glutamine or arginine availability preferentially modulated the release of CXCL9 and Galectin-9 from peripheral blood mononuclear cells of patients with AID-CA. Together, these findings define an internally consistent immunometabolic pattern associated with cancer comorbidities in patients with AIDs. They nominated amino acid metabolism and CXCL9/Galectin-9-centered immune signaling as candidates for mechanistic investigation and biomarker development, while underscoring the need for validation in larger, longitudinal, and disease-specific cohorts.

To explore the risk of relapse after glucocorticoids (GCs) withdrawal in patients with stable Sjögren’s disease-associated interstitial lung disease (SjD-ILD). This was a single-center, retrospective cohort study conducted at Peking Union Medical College Hospital between February 2016 and January 2024. The study compared two treatment strategies for patients with stable SjD-ILD: GC withdrawal versus GC maintenance. The primary endpoint was to compare the relapse rates between the two groups over a 3-year follow-up period. The secondary endpoints included changes in pulmonary function, serological markers, and adverse events. A total of 134 patients were included in this study, with 61 in the GC withdrawal group and 73 in the GC maintenance group. Over the 3-year follow-up, 16 patients (27.93

Rheumatoid arthritis (RA) is an aggressive, systemic autoimmune disease in which overactivated macrophages play a critical role in its pathogenesis. This study aimed to explore the potential role of glycolytic reprogramming in the production of proinflammatory cytokines by macrophages in RA. The Seahorse assay was conducted on RA or healthy control (HC) serum-treated human monocyte-derived macrophages (HMDMs) to evaluate glycolysis levels. RNA sequencing was performed to identify activated signaling pathways and key molecules in HMDMs stimulated by RA serum. The proinflammatory cytokines and hypoxia-inducible factor 1α (HIF-1α) were verified by Western blotting and quantitative polymerase chain reaction (qPCR). We found that HMDMs stimulated with RA serum showed higher aerobic glycolysis levels than those treated with HC serum, along with higher expression of glycolysis-related genes, including hexokinase2 (HK2), pyruvate kinase L/R (PKLR), and phosphoglycerate kinase 1 (PGK1). Furthermore, RA serum-treated macrophages exhibited a higher level of interleukin-1 beta (IL-1β), and the expression of IL-1β positively correlated with HK2. Inhibition of glycolysis by 3-bromopyruvate (3BrPA) or HK2 knockdown significantly suppressed IL-1β production in macrophages. The HIF-1α-associated signaling pathways and HIF-1α protein levels were also elevated in RA serum-treated macrophages. Inhibition of glycolysis by 3BrPA or knockdown of HK2 reduced HIF-1α. Inhibiting HIF-1α can suppress IL-1β production of RA serum-treated macrophages, and vice versa. TNF-α and IL-1β enhanced HIF-1α and IL-1β expression in macrophages, an effect attenuated by glycolysis inhibition. Blocking TNF-α and IL-1β in RA serum diminished both glycolysis and IL-1β production. Our findings demonstrate that RA serum triggers aerobic glycolysis in macrophages, which promotes HIF-1α to drive IL-1β production. Notably, IL-1β within RA serum amplifies its own expression via this glycolysis-HIF-1α axis, establishing a pathogenic positive feedback loop in RA.

This study aimed to compare the value of [68 Ga]Ga-FAPI-04 PET/CT with X-ray imaging in assessing disease activity and treatment response in patients with rheumatoid arthritis (RA). All patients underwent clinical and laboratory assessments, [68 Ga]Ga-FAPI-04 PET/CT, and X-ray imaging, with a 6-month follow-up to assess disease activity and treatment response. Bland–Altman analysis assessed the agreement between PET/CT and X-ray parameters. Correlation analyses were performed between clinical characteristics and imaging parameters. Receiver operating characteristic (ROC) curve analyses were used to predict treatment response. We prospectively enrolled 17 patients with RA (14 females and 3 males; median age, 55.0 yr [IQR: 50.0–58.5 yr]). [68 Ga]Ga-FAPI-04 PET/CT showed strong agreement with X-ray in evaluating the number of joints involved. PET/CT imaging-derived parameters, including PET joint count (PJCFAPI), PET articular index (PAIFAPI), total synovitis uptake (TSUFAPI), and metabolic synovitis volume (MSVFAPI) were significantly correlated with C-reactive protein levels. Moreover, PJCFAPI and PAIFAPI were associated with tender or swollen joint count (TJC/SJC), disease activity score with 28-joint counts (DAS28), and Simplified Disease Activity Index (SDAI), respectively. No correlations were observed between the X-ray findings and disease activity parameters. The baseline PAIFAPI > cutoff values could discriminate responders and non-responders at the 6-month follow-up according to the Clinical Disease Activity Index (CDAI) and SDAI response criteria, while X-ray could not predict treatment response. [68 Ga]Ga-FAPI-04 PET/CT was superior to X-ray imaging in evaluating disease activity and predicting treatment response in patients with RA. ClinicalTrials. NCT04514614. Registered 13 August 2020, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000A4PN selectaction=Edit uid=U0001JRW ts=2 cx=-×9t7p

ABSTRACTObjectiveThis study aimed to investigate the mortality, survival rates, and prognostic indicators of cancer occurrence after Sjögren's syndrome (SS‐CA).MethodsThe medical records of patients with SS‐CA at the Peking Union Medical College Hospital (PUMCH) between January 2010 and August 2022 were retrieved. Clinical data and survival outcomes were compared to controls. The standard mortality ratio (SMR) versus the general population was calculated, and the survival and predictive markers of prognosis were analyzed using Kaplan–Meier curves and Cox regression.ResultsIn total, 114 SS‐CA patients were included, with a median follow‐up time of 105.1 (57.3–168.0) months. Non‐Hodgkin lymphoma (32, 28.1%) was the most common cancer in patients with SS‐CA. The SMR of SS‐CA patients was 2.61 (95% confidence interval [CI] 1.73–3.77). Patients with SS‐CA exhibited significantly inferior outcomes compared to controls (p = 0.010), with 5‐ and 10‐year overall survival rates of 91.2% and 83.2%, respectively. SS patients with a diagnostic interval between SS and cancer (SS‐CA diagnostic interval) ≤ 3 years or with hematological malignancies had poorer survival compared to those with a diagnostic interval > 3 years (p < 0.001) or with solid tumors (p = 0.019). Multivariate Cox regression analysis identified the prognosis‐associated factors of SS‐CA as age at SS diagnosis > 50 years (HR 3.129, 95% CI 1.224–7.998; p = 0.017), SS‐CA diagnostic interval ≤ 3 years (HR 7.754, 95% CI 1.953–30.781; p = 0.004), and hematological malignancies (HR 2.648, 95% CI 1.201–5.838; p = 0.016).ConclusionMalignant comorbidities constituted a poor prognosis in patients with SS, wherein the SS‐CA diagnostic interval and the types of cancer were associated with survival.

BACKGROUND:The dynamics of peripheral immune cells during the development of immune-related adverse events (irAEs) remain incompletely characterized, underscoring the need to elucidate their temporal patterns to uncover immune disturbances and identify biomarkers. METHODS:In this prospective study, patients with lung cancer receiving immune checkpoint inhibitors (ICIs) were enrolled at Peking Union Medical College Hospital and were consecutively followed up for the development of irAEs. Comprehensive immune profiling by multicolor flow cytometry of peripheral blood samples collected at baseline (T0), early (T1, 1-3 weeks) and late (T2, 3-6 months) treatment, and at the onset of irAE (Tae) was performed. We utilized Mfuzz clustering analysis to characterize immune cell trajectories and calculated the change in cell frequencies (ΔT) from T0 to subsequent time points (ΔTae, ΔT1, and ΔT2) to identify time-dependent immune signatures predictive of irAE occurrence, severity, and specific organ involvement. RESULTS:Among the 60 lung cancer patients who received ICIs, 26 (43.3 %) developed irAEs. Mfuzz clustering highlighted the distinct dynamics of CD8mid T cells and CD14+CD16-HLA-DRhi monocytes during ICIs therapy. During early treatment, the irAE group showed a greater increase in CD8+CTLA-4+ T cells and greater reductions in both total CD8+ T cells and double-negative B (DNB) cells. At ΔT2, the irAE group exhibited significantly greater alterations in CD4+CD25+ T cells, CD4+HLA-DR+ T cells, CD14+CD16-HLA-DRhi monocytes, and CD8mid T cells. At ΔTae, patients with irAEs exhibited a significant expansion of non-switched memory (NSM) B cells and a reduction in CD3+ T cells, whereas non-irAE patients showed opposite trends. Stratified analysis confirmed that the ΔT of NSM B cells, CD8+CTLA-4+ T cells, DNB cells, CD4+CD25+ T cells, and CD14+CD16-HLA-DRhi monocytes aligned with both clinical severity and specific organ involvement of irAEs. CONCLUSION:The distinct dynamics of cellular signatures during irAEs development provide potential biomarkers associated with the development of irAEs and shed novel insights into immune disturbance.

Primary Sjögren’s syndrome (pSS) is a prevalent autoimmune disorder wherein CD4+ T cells play a pivotal role in its pathogenesis. However, the underlying mechanisms driving the hyperactivity of CD4+ T cells in pSS remain poorly understood. This study aimed to investigate the potential role of immunometabolic alterations in driving the hyperactivity of CD4+ T cells in pSS. We employed Seahorse XF assay to evaluate the metabolic phenotype of CD4+ T cells, conducted flow cytometry to assess the effector function and differentiation of CD4+ T cells and measured the level of intracellular reactive oxygen species (ROS). Additionally, transcriptome sequencing, PCR, and Western blotting were utilized to examine the expression of glycolytic genes. Our investigation revealed that activated CD4+ T cells from pSS patients exhibited elevated aerobic glycolysis, rather than oxidative phosphorylation, resulting in excessive production of IFN-γ and IL-17A. Inhibition of glycolysis by 2-Deoxy-D-glucose reduced the expression of IFN-γ and IL-17A in activated CD4+ T cells and mitigated the differentiation of Th1 and Th17 cells. Furthermore, the expression of glycolytic genes, including CD3E, CD28, PIK3CA, AKT1, mTOR, MYC, LDHA, PFKL, PFKFB3, and PFKFB4, was upregulated in activated CD4+ T cells from pSS patients. Specifically, the expression and activity of LDHA were enhanced, contributing to an increased level of intracellular ROS. Targeting LDHA with FX-11 or inhibiting ROS with N-acetyl-cysteine had a similar effect on reversing the dysfunction of activated CD4+ T cells from pSS patients. Our study unveils heightened aerobic glycolysis in activated CD4+ T cells from pSS patients, and inhibition of glycolysis or its metabolite normalizes the dysfunction of activated CD4+ T cells. These findings suggest that aerobic glycolysis may be a promising therapeutic target for the treatment of pSS.

Microbes play a significant role in human tumor development and profoundly impact treatment efficacy, particularly in immunotherapy. The respiratory tract extensively interacts with the external environment and possesses a mucosal immune system. This prompts consideration of the relationship between respiratory microbiota and lung cancer. Advancements in culture-independent techniques have revealed unique communities within the lower respiratory tract. Here, we provide an overview of the respiratory microbiota composition, dysbiosis characteristics in lung cancer patients, and microbiota profiles within lung cancer. We delve into how the lung microbiota contributes to lung cancer onset and progression through direct functions, sustained immune activation, and immunosuppressive mechanisms. Furthermore, we emphasize the clinical utility of respiratory microbiota in prognosis and treatment optimization for lung cancer.

Due to the advancement of 16S rRNA sequencing technology, the lower respiratory tract microbiota, which was considered non-existent, has been revealed. The correlation between these microorganisms and diseases such as tumor has been a hot topic in recent years. As the bacteria in the surrounding can infiltrate the tumors, researchers have also begun to pay attention to the biological behavior of tumor bacteria and their interaction with tumors. In this review, we present the characteristic of the lower respiratory tract bacteria and summarize recent research findings on the relationship between these microbiota and lung cancer. On top of that, we also summarize the basic feature of bacteria in tumors and focus on the characteristic of the bacteria in lung cancer. The relationship between bacteria in lung cancer and tumor development is also been discussed. Finally, we review the potential clinical applications of bacterial communities in the lower respiratory tract and lung cancer, and summarize key points of sample collection, sequencing, and contamination control, hoping to provide new ideas for the screening and treatment of tumors.

The increase in the detection rate of synchronous multiple primary lung cancer (MPLC) has posed remarkable clinical challenges due to the limited understanding of its pathogenesis and molecular features. Here, comprehensive comparisons of genomic and immunologic features between MPLC and solitary lung cancer nodule (SN), as well as different lesions of the same patient, were performed. Compared with SN, MPLC displayed a lower rate of EGFR mutation but higher rates of BRAF, MAP2K1, and MTOR mutation, which function exactly in the upstream and downstream of the same signaling pathway. Considerable heterogeneity in T cell receptor (TCR) repertoire exists among not only different patients but also among different lesions of the same patient. Invasive lesions of MPLC exhibited significantly higher TCR diversity and lower TCR expansion than those of SN. Intriguingly, different lesions of the same patient always shared a certain proportion of TCR clonotypes. Significant clonal expansion could be observed in shared TCR clonotypes, particularly in those existing in all lesions of the same patient. In conclusion, this study provided evidences of the distinctive mutational landscape, activation of oncogenic signaling pathways, and TCR repertoire in MPLC as compared with SN. The significant clonal expansion of shared TCR clonotypes demonstrated the existence of immune commonality among different lesions of the same patient and shed new light on the individually tailored precision therapy for MPLC.

Inflammatory arthritis (IA) is a common rheumatic adverse event following immune checkpoint inhibitors treatment. The clinical disparities between IA and rheumatoid arthritis (RA) imply disease heterogeneity and distinct mechanisms, which remain elusive. Here, we profile CD45 + cells from the peripheral blood or synovial fluid (SF) of patients with PD-1-induced IA (PD-1-IA) or RA using single-cell RNA sequencing. We report the predominant expansion of IL1B hi myeloid cells with enhanced NLRP3 inflammasome activity, in both the SF and peripheral blood of PD-1-IA, but not RA. IL1B hi macrophages in the SF of PD-1-IA shared similar inflammatory signatures and might originate from peripheral IL1B hi monocytes. Exhausted CD8 + T cells (Texs) significantly accumulated in the SF of patients with PD-1-IA. IL1B hi myeloid cells communicated with CD8 + Texs possibly via the CCR1-CCL5/CCL3 and CXCL10-CXCR3 axes. Collectively, these results demonstrate different cellular and molecular pathways in PD-1-IA and RA and highlight IL1B hi macrophages as a possible therapeutic target in PD-1-IA.

OBJECTIVE:This study aimed to classify idiopathic inflammatory myopathy (IIM) patients with cardiac involvement (IIM-CI) into different categories based on their clinical phenotypes via cluster analysis and to explore their differences in outcomes.METHODS:IIM-CI patients admitted to Peking Union Medical College Hospital from January 2015 to June 2021 were retrieved. The clinical data, laboratory examinations, and treatment were retrospectively reviewed, and the outcome was traced. A second-order clustering method was employed for categorization.RESULTS:A total of 88 IIM-CI patients were enrolled in this study and were classified into two categories through cluster analysis. Category I consisted of patients who exhibited distinct cardiac structural and functional changes, such as enlargement of atriums and/or ventricles, along with the remarkable heart insufficiency biomarkers, whereas patients of category II displayed more widely systemic injuries and intensive skeletal muscle weakness. In comparison, pulmonary hypertension (58.8% vs 16.7%, p < 0.01), arrhythmia (82.4% vs 27.8%, p < 0.01), and positive serum anti-mitochondrial-M2 antibody (52.9% vs 5.6%, p < 0.01) were more prevalent in category I than in category II, and serum N-terminal pro-B-type natriuretic peptide levels (1703.5 pg/L vs 364.0 pg/L, p = 0.02) were significantly elevated in category I, whereas skeletal muscle weakness (50.0% vs 74.1%, p = 0.02), interstitial lung disease (20.6% vs 63.0%, p < 0.01), skin rash (11.8% vs 48.1%, p < 0.01), arthralgia (2.9% vs 27.8%, p < 0.01), fever (2.9% vs 27.8%, p < 0.01), and dysphagia (2.9% vs 22.2%, p < 0.01) were more common in category II patients. Heart failure was the primary cause of death in category I, but severe pneumonia was predominantly responsible for deaths in category II.CONCLUSION:Two categories of IIM-CI were identified based on clinical features with distinctive characteristics. Two categories exhibited differences in clinical manifestations, autoantibody profiles, and the primary cause of death.

Background The identification of biomarkers predicting the treatment response of rheumatoid arthritis (RA) is important. [ 68 Ga]Ga-FAPI-04 showed markedly increased uptake in the joints of patients with RA. The purpose of this study is to investigate whether [ 68 Ga]Ga-FAPI-04 PET/CT can be a predictor of treatment response in RA. Results Nineteen patients diagnosed with RA in the prospective cohort study were finally enrolled. Both total synovitis uptake (TSU) and metabolic synovitis volume (MSV) in [ 68 Ga]Ga-FAPI-04 and [ 18 F]FDG PET/CT of the responders were significantly higher than those in non-responders according to Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) response criteria at 3-months’ follow-up ( P < 0.05). The PET joint count (PJC) detected in [ 68 Ga]Ga-FAPI-04 and [ 18 F]FDG PET/CT were also significantly higher in CDAI responders than non-responders ( P = 0.016 and 0.045, respectively). The clinical characteristics of disease activity at baseline did not show significant difference between the responders and non-responders, except CRP ( P = 0.035 and 0.033 in CDAI and SDAI response criteria, respectively). The baseline PJC FAPI , TSU FAPI and MSV FAPI > cutoff values in [ 68 Ga]Ga-FAPI-04 PET/CT successfully discriminated CDAI and SDAI responders and non-responders at 3-months’ follow-up. Conclusion [ 68 Ga]Ga-FAPI-04 uptake at baseline were significantly higher in early responders than those in non-responders. Trial registration ClinicalTrials. NCT04514614. Registered 13 August 2020, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000A4PN&selectaction=Edit&uid=U0001JRW&ts=2&cx=-x9t7cp

AbstractBackgroundLung adenocarcinoma (LUAD) is the most common type of lung cancer and closely associated with the immune system. Emerging evidence suggests that blood immune cell phenotypes in patients with LUAD may undergo alterations. Nevertheless, the limited amount of relevant research makes it difficult to understand the causal links between LUAD and changes in the immune cells. This study aimed to reveal the potential causal relationships between 731 immune cell phenotypes and LUAD.MethodsA bidirectional two‐sample Mendelian randomization (MR) analysis was used to clarify causal relationships. Four types of immune phenotypes, absolute cell counts, relative cell counts, median fluorescence intensities (MFIs) of surface antigens, and morphological parameters, were investigated in this study. Heterogeneity tests, horizontal pleiotropy tests, and leave‐one‐out analyses were performed to validate the reliability of our study.ResultsA total of 26 immune cell characteristics were identified as contributing to the occurrence of LUAD. Memory B cells, IgD−CD38br cells, CD4+ regulatory T cells (Tregs), and plasmacytoid dendritic cells (DCs) may play a role in the development of LUAD. Through reverse MR, our study discovered that the presence of LUAD also induced changes in the expression levels of 16 immune cell traits involving specific surface markers and various types of immune cells, some of which pertain to antigen presentation and immune activation processes.ConclusionOur study demonstrated causal links between several immune cell phenotypes and LUAD, thereby providing indications of the potentially oncogenic physiological state and early screening biomarkers for future research.