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Liver cancer is a leading cause of cancer-related deaths in the United States. The composition of the gut microbiome influences many human diseases, including liver inflammatory disorders. Ma et al. found that commensal gut bacteria can recruit the immune system to control the growth of liver tumors in mice (see the Perspective by Hartmann and Kronenberg). Clostridium species modified bile acids to signal liver sinusoidal endothelial cells to produce the chemokine CXCL16. This recruited natural killer T (NKT) immune cells to perform antitumor surveillance of the liver. Growth of both primary and metastatic cancer was reduced by NKT cell–driven killing. Science , this issue p. eaan5931 ; see also p. 858 Cross-talk between bacteria and bile acid promotes natural killer T cell antitumor immunity in the liver. Primary liver tumors and liver metastasis currently represent the leading cause of cancer-related death. Commensal bacteria are important regulators of antitumor immunity, and although the liver is exposed to gut bacteria, their role in antitumor surveillance of liver tumors is poorly understood. We found that altering commensal gut bacteria in mice induced a liver-selective antitumor effect, with an increase of hepatic CXCR6 + natural killer T (NKT) cells and heightened interferon-γ production upon antigen stimulation. In vivo functional studies showed that NKT cells mediated liver-selective tumor inhibition. NKT cell accumulation was regulated by CXCL16 expression of liver sinusoidal endothelial cells, which was controlled by gut microbiome-mediated primary-to-secondary bile acid conversion. Our study suggests a link between gut bacteria–controlled bile acid metabolism and liver antitumor immunosurveillance.

Follicular helper T cells (Tfh) are a Th cell subset that directly assists B cells in functioning, and their development is regulated by various factors. Among them, the initial regulation leads to phenotypic heterogeneity, while the regulation of their migration process results in spatial heterogeneity. The phenotypic heterogeneity is manifested by the presence of Tfh subsets with characteristics helper T cells (Th) of other lineages, namely Tfh1, Tfh2, and Tfh17, with different transcriptional programs and secrete distinct cytokines, potentially possessing different functions. The spatial heterogeneity is mainly manifested by the positional relationship between Tfh and germinal centers (GC), which are mainly divided into GC-Tfh, follicular mantle Tfh, and circulating Tfh, possibly reflecting the process of Tfh occurrence. This review summarizes the spatial and phenotypic heterogeneity of Tfh cells, and suggests a Tfh cell type framework with nodes of previous studied cell types and the edges of switching between specific celltypes, which is affected by the summation of imprinted plasticity part and de novo plasticity part in Tfh development, connecting the hypothesis Crotty et al. proposed in 2018. Discrete cell type is still eligible in qualifying the diseases state and quantifying the activity and severity of diseases, but it could also be beneficial to look Tfh from the view of cell states and expression programs, which, in the future studies, might better model the through process of Tfh development and unifying the contradiction caused by separate Tfh cell type view.

To assess the efficacy and safety of eltrombopag in connective tissue disease (CTD)-immune thrombocytopenia (ITP), we conducted this single-center retrospective observational study, including patients with refractory CTD-ITP who were treated with eltrombopag between January 2018 and August 2019. The characteristics of patients at baseline, and the efficacy and safety of the drug were analyzed. The predictors for a response were analyzed using a univariate analysis such as Chi-square or nonparametric test and a multiple correspondence analysis (MCA) method. A total of 15 patients with refractory CTD-ITP were included in the study. Their median age at the time of inclusion was 40.6 years. The median platelet count at initiation of eltrombopag was 11.53 × 10 9 /L. The median remission time was 3.42 weeks. The complete remission (CR) and overall response rate decreased with time. The factors that associated with response to eltrombopag in patients with CTD-ITP were protopathy, WBC counts, levels of hemoglobin, and characteristics of bone marrow findings in univariate analysis. In addition, MCA indicated that a poor response to eltrombopag in patients with refractory CTD-ITP was closely associated with a protopathy with SS, medium to severe degree of anemia, leukopenia, and bone marrow aspiration showing aplastic anemia, an absence of megakaryocytes or macrophage activation syndrome (MAS). In conclusion, eltrombopag was effective and well-tolerated in patients with CTD-associated thrombocytopenia. Some factors should be considered in the use of eltrombopag, including the protopathy, blood test, and bone marrow histology.

Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5 + DM) is an autoimmune condition associated with rapidly progressive interstitial lung disease and high mortality. The aetiology and pathogenesis of MDA5 + DM are still largely unknown. Here we describe the immune signatures of MDA5 + DM via single-cell RNA sequencing, flow cytometry and multiplex immunohistochemistry in peripheral B and T cells and in affected lung tissue samples from one patient. We find strong peripheral antibody-secreting cell and CD8 + T cell responses as cellular immune hallmarks, and over-stimulated type I interferon signaling and associated metabolic reprogramming as molecular immune signature in MDA5 + DM. High frequency of circulating ISG15 + CD8 + T cells at baseline predicts poor one-year survival in MDA5 + DM patients. In affected lungs, we find profuse immune cells infiltration, which likely contributes to the pro-fibrotic response via type I interferon production. The importance of type I interferons in MDA5 + DM pathology is further emphasized by our observation in a retrospective cohort of MDA5 + DM patients that combined calcineurin and Janus kinase inhibitor therapy show superior efficacy to calcineurin inhibitor monotherapy. In summary, this study reveals key immune-pathogenic features of MDA5 + DM and provides a potential basis for future tailored therapies. Anti-melanoma differentiation-associated gene 5-positive dermatomyositis is a severe autoimmune disease with largely unknown aetiology. Here authors identify the key immune cell types that contribute to the disease phenotype and implicate type I interferons signalling in the patho-mechanism.

Upper digestive tract cancers, such as oral cavity, laryngeal, esophageal, and gastric cancers, account for 10% of cancer cases and 14.5% of cancer-related deaths worldwide. Conventional treatments often provide limited survival benefits and are frequently associated with adverse effects and drug resistance. Chinese herbal drugs (CHDs) are widely used in the Far East for managing these cancers. In this narrative review, we summarize current clinical studies (published up to June 2024) on the use of 138 CHDs in the treatment of cancers and precancerous lesions of the upper digestive tract. For cancer treatment, 126 CHDs were tested, all in combination with conventional therapies. Each CHD increased the clinical efficacy and/or reduced the adverse effects of conventional therapies. The five-year survival rate is a critical metric for evaluating the clinical benefits of cancer treatments. Four of the CHDs were reported to increase five-year survival rates of patients receiving conventional therapies. The four CHDs are Sishen Jiedu Decoction, Pingxiao Tablet, Fuzheng Guben Granule, and Buyang Huanwu Tang. For managing precancerous lesions, 12 CHDs were tested: six used alone and six in combination with conventional therapies. Zengshengping is one of the CHDs used alone and is the only one that has been proven to prevent the development of esophageal cancer with convincing evidence. This review provides information about the clinical benefits of CHDs and offers a reference for their rational application in treating upper digestive tract cancers. The reviewed studies have limitations: most trials had small sample sizes and were not multi-center; only one study investigated the mechanisms of action of the studied CHD; and the active components of CHDs were not explored. To promote international recognition of CHDs, rigorously designed studies on clinical outcomes, mechanisms of action, and active components are warranted. Moreover, the studied CHDs should be standardized.

Abstract The remarkable efficacy of chimeric antigen receptor (CAR) T cell therapy in hematological malignancies has provided a solid basis for the therapeutic concept, wherein specific pathogenic cell populations can be eradicated by means of targeted recognition. During the past few years, CAR-based cell therapies have been extensively investigated in preclinical and clinical research across various non-tumor diseases, with particular emphasis in the treatment of autoimmune diseases (ADs), yielding significant advancements. The recent deployment of CD19-directed CAR T cells has induced long-lasting, drug-free remission in patients with systemic lupus erythematosus (SLE) and other systemic ADs, alongside a more profound immune reconstruction of B cell repertoire compared with conventional immunosuppressive agents and B cell-targeting biologics. Despite the initial success achieved by CAR T cell therapy, it is critical to acknowledge the divergences in its application between cancer and ADs. Through examining recent clinical studies and ongoing research, we highlight the transformative potential of this therapeutic approach in the treatment of SLE, while also addressing the challenges and future directions necessary to enhance the long-term efficacy and safety of CAR-based cell therapies in clinical practice.

Background Idiopathic inflammatory myopathies (IIM) are associated with a significantly higher risk of opportunistic infections including Pneumocystis jirovecii pneumonia (PJP), a potentially fatal opportunistic infection. However, no prior studies have evaluated PJP infection in subtypes of IIM. Objectives To investigate the prevalence and mortality rate of PJP infection in subgroups of IIM patients stratified according to myopathy-specific antibodies. Methods In the first part of the study, 463 consecutive patients with IIM were prospectively followed for a period of at least 1 year to analyze the incidence of PJP. In the second part of the study, we enrolled 30 consecutive PJP patients with any rheumatic disease in order to identify the mortality rate and risk factors by Cox regression analysis. The Kaplan-Meier method with log-rank testing was used to assess differences in survival. Results The prevalence of PJP in IIM patients was found to be 3.0/100 person-years, while in MDA5 + DM patients it was 7.5/100 person-years and in MDA5 − IIM patients 0.7/100 person-years ( P < 0.05). PJP typically occurred in the first 2 months in the case of MDA5 + DM patients who had a significant decrease in their CD4 + T cell counts and lymphocyte counts ( P < 0.05). In PJP patients, 3-month mortality was higher for MDA5 + DM patients than in those with other rheumatic diseases (83.3% vs 38.9%, P < 0.05). Alarmingly, MDA5 + DM patients seemed not to benefit from prompt anti-PJP treatment, unlike patients with other rheumatic diseases whose survival improved when anti-PJP treatment was started within 6 days ( P < 0.05). Conclusion PJP has an alarming high incidence and mortality in MDA5 + DM patients. Timely treatment for PJP seems not to improve the prognosis of patients with this particular subtype. Hence, there remains a crucial unmet need to develop PJP prophylaxis for MDA5 + DM patients.

To investigate the clinical significance of the interferon (IFN) score, especially the IFN-I score, in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (anti-MDA5 DM). We enrolled 262 patients with different autoimmune diseases, including idiopathic inflammatory myopathy, systemic lupus erythematosus, rheumatoid arthritis, adult-onset Still's disease, and Sjögren's syndrome, as well as 58 healthy controls. Multiplex quantitative real-time polymerase chain reaction (RT-qPCR) using four TaqMan probes was used to evaluate type I IFN-stimulated genes (IFI44 and MX1), one type II IFN-stimulated gene (IRF1), and one internal control gene (HRPT1), which were used to determine the IFN-I score. The clinical features and disease activity index were compared between the high and low IFN-I score groups in 61 patients with anti-MDA5+ DM. The associations between laboratory findings and the predictive value of the baseline IFN-I score for mortality were analyzed. The IFN score was significantly higher in patients with anti-MDA5+ DM than in healthy controls. The IFN-I score was positively correlated with the serum IFN-α concentration, ferritin concentration, and Myositis Disease Activity Assessment Visual Analogue Scale (MYOACT) score. Compared with patients with a low IFN-I score, patients with a high IFN-I score showed a higher MYOACT score, C-reactive protein concentration, aspartate transaminase concentration, ferritin concentration, plasma cell percentage, and CD3+ T-cell percentage, as well as lower lymphocyte, natural killer cell, and monocyte counts. The 3-month survival rate was significantly lower in patients with an IFN-I score of >4.9 than in those with an IFN-I score of ≤4.9 (72.9% . 100%, respectively; P = 0.044). The IFN score, especially the IFN-I score, measured by multiplex RT-qPCR is a valuable tool to monitor disease activity and predict mortality in patients with anti-MDA5+ DM.

ObjectivesA population of atypical memory B cells (AtMs) are greatly expanded in patients with active lupus, but their generation and pathophysiological roles are poorly defined. The aim of this study was to comprehensively characterise lupus AtMs with a purpose to identify therapeutic clues to target this B cell population in lupus.MethodsPeripheral B cell subsets were measured by flow cytometry. Sorting-purified B cell subsets were subject to RNA sequencing and functional studies. Plasma cytokines and secreted immunoglobulins were detected by Luminex or ELISA. In situ renal B cells were detected by multiplexed immunohistochemistry.ResultsCD24−CD20hi AtMs were strongly increased in two Chinese cohorts of patients with treatment-naïve lupus. Gene expression profile indicated that B cell signalling and activation, lipid/saccharide metabolism and endocytosis pathways were abnormally upregulated in lupus AtMs. In addition, the mammalian target of rapamycin complex 1 (mTORC1) pathway was remarkably activated in lupus AtMs, and blocking mTORC1 signalling by rapamycin abolished the generation of T-bet+ B cells and terminal differentiation of lupus AtMs. Furthermore, lupus AtMs displayed a dysfunctional phenotype, underwent accelerated apoptosis, poorly co-stimulated T cells and produced proinflammatory cytokines. Interestingly, lupus AtMs were in a paradoxically differentiated status with markers pro and against terminal differentiation and enriched with antinucleosome reactivity. Finally, AtMs were accumulated in the kidneys of patients with lupus nephritis and associated with disease severity.ConclusionsThese findings demonstrated that mTORC1-overactivated lupus AtMs are abnormally differentiated with metabolic and functional dysregulations. Inhibiting mTORC1 signalling might be an attractive option to target AtMs and to improve therapeutic effectiveness in patients with lupus.