Biomarker Research最新文献

Background: Although immunotherapy has achieved great progress in advanced triple-negative breast cancer (TNBC), there are still numerous patients who do not benefit from immunotherapy. Therefore, identification of the key molecule that induces immune escape and clarification of its specific mechanism in TNBC are urgently needed.

Methods: In this research, single cell sequencing and bulk sequencing were conducted for biomarker screening. Immunohistochemistry, multiplex immunofluorescence, and orthotopic TNBC tumor model were applied in identifying the key molecule driving immune escape. At the mechanical level, RNA sequencing, in vitro co-culturing system, flow cytometry, Western blotting, ELISA, and real-time qPCR were carried out.

Results: Mortality factor 4 like 2 (MORF4L2) expression is significantly up-regulated among patients who developed anti-PD1 resistance. MORF4L2 enhances anti-PD1 resistance by inducing the chemotaxis of macrophage infiltration and promoting their polarization towards the alternative activation phenotype (M2), thus creating an immunosuppressive microenvironment. Mechanistically, MORF4L2 actes as part of NuA4 histone acetyltransferase (HAT) complex, contributes to to histone 4 lysine 12 acetylation (H4K12Ac) and activates the downstream transcription of macrophage colony-stimulating factor (CSF1). CSF1 is secreted by tumor cells and binds to the macrophage-surface CSF1 receptor (CSF1R), which chemotactically converted and polarized macrophages to the M2 phenotype. Furthermore, we revealed that grainyhead like transcription factor 2 (GRHL2) could promote MORF4L2 transcription by binding to the MORF4L2 enhancer region. Notably, BLZ549, an inhibitor of CSF1R, restored the anti-PD1 sensitivity by blocking the GRHL2/MORF4L2/H4K12Ac/CSF1 axis.

Conclusions: GRHL2/MORF4L2/H4K12Ac/CSF1 axis plays an important role in anti-PD1 resistance. CSF1R inhibitors can reverse GRHL2/MORF4L2-mediated anti-PD1 resistance.

Background: Up to 23% of breast cancer patients recurred within a decade after trastuzumab treatment. Conversely, one trial found that patients with low HER2 expression and metastatic breast cancer had a positive response to trastuzumab-deruxtecan (T-Dxd). This indicates that relying solely on HER2 as a single diagnostic marker to predict the efficacy of anti-HER2 drugs is insufficient. This study highlights the interaction between histamine N-methyltransferase (HNMT) and HER2 as an adjunct predictor for trastuzumab response. Furthermore, modulation of HER2 expression by HNMT may explain why those with low HER2 expression still respond to T-Dxd.

Methods: We investigated the impact of HNMT protein expression on the efficacy of anti-HER2 therapy in both in vivo and ex vivo models of patient-derived xenografts and cell line-derived xenografts. Our analysis included Förster resonance energy transfer (FRET) to assess the interaction strength between HNMT and HER2 proteins in trastuzumab-resistant and sensitive tumor tissues. Additionally, we used fluorescence lifetime imaging microscopy (FLIM), cleaved luciferase, and immunoprecipitation to study the interaction dynamics of HNMT and HER2. Furthermore, we evaluated the influence of HNMT activity on the binding of anti-HER2 antibodies to their targets through flow cytometry. We also observed the nuclear translocation of HNMT/HER2-ICD cells using fluorescent double staining and DeltaVision microscopy. Finally, ChIP sequencing was employed to identify target genes affected by the HNMT/HER2-ICD complex.

Results: This study highlights HNMT as a potential auxiliary biomarker for diagnosing HER2 + breast cancer. FRET analysis demonstrated a significant interaction between HNMT and HER2 protein in trastuzumab-sensitive tumor tissue (n = 50), suggesting the potential of HNMT as a predictor of treatment response. Mechanistic studies revealed that the interaction between HNMT and HER2 contributes to increased HER2 protein expression at the transcriptional level, thereby impacting the efficacy of anti-HER2 therapy. Furthermore, a subset of triple-negative breast cancers characterized by HNMT overexpression was found to be sensitive to HER2 antibody-drug conjugates such as T-Dxd.

Conclusions: These findings offer crucial insights for clinicians evaluating candidates for anti-HER2 therapy, especially for HER2-low breast cancer patients who could gain from T-Dxd treatment. Identifying HNMT expression could help clinicians pinpoint patients who would benefit from anti-HER2 therapy.

Background: Oncolytic viruses (OVs) are increasingly recognized as promising tools for cancer therapy, as they selectively infect and destroy tumor cells while leaving healthy cells unharmed. Despite considerable progress, the limited therapeutic efficacy of OV-based virotherapy continues to be a significant challenge in cancer treatment.

Methods: The SMAC/DIABLO gene was inserted into the genome of vesicular stomatitis virus (VSV) to generate VSV-S. Head and neck squamous cell carcinoma (HNSCC) cell lines and orthotopic mouse models were employed for research. Morphological changes were observed using both light microscopy and transmission electron microscopy. Molecular alterations were analyzed through Western blotting and ELISA kits. The tumor secretome was characterized using a combination of biotinylation and LC-MS analysis. Immune cell changes were evaluated by flow cytometry and immunohistochemistry.

Results: Compared to its parental virus, VSV-S not only increases apoptosis by overexpressing SMAC during VSV infection but also triggers elevated levels of PANoptosis (pyroptosis, apoptosis, and necroptosis) in HNSCC cells via activation of caspase-1/gasdermin D (GSDMD) signaling. As a result, VSV-S-induced PANoptosis promotes CD8⁺ T cell tumor infiltration and enhances their cytotoxic capacity, eventually potentiating T cell-mediated antitumor immunity. Moreover, VSV-S reduces PDL1 levels in HNSCC cells and, in combination with PD1 blockade, produces a more potent antitumor effect than either therapy alone.

Conclusions: Our findings demonstrate that the combination of VSV-S and PD1 blockade offers a synergistic therapeutic strategy for HNSCC, supporting the advancement of VSV-based virotherapy as a promising strategy to improve outcomes for HNSCC patients.

FMS-like tyrosine kinase 3 (FLT3) genetic variants are commonly seen in high-grade myeloid neoplasms and are typically gain-of-function mutations associated with a proliferative disease phenotype. Inactivating FLT3 variants have been less frequently described in non-malignant, autoimmune disorders and are uncommon in aplastic anemia (AA). Herein, we report the first to our knowledge, and unusual case of a germline, gain-of-function, FLT3 variant in a patient with severe AA treated successfully with immunosuppressive therapy. Although a proposed link between dysregulated FLT3 signaling and autoimmunity has been described and could be speculated in the case of AA, it is currently unknown whether a pathogenetic connection between an activating germline FLT3 variant and AA truly exists and whether the mutation signifies a lifelong risk of disease recurrence and/or clonal evolution. However, the recognition of the FLT3 gene as subject not only to somatic but also germline mutations is the first step in interrogating its functional implications. Further study of unusual genotype-phenotype combinations, such as in the case presented, may shed light on a potential pathogenetic link.

Background and objective: Gastric cancer (GC) remains a significant global health challenge, characterized by high incidence and mortality rates, particularly in East Asia. A comprehensive understanding of the disease burden of gastric cancer is crucial for developing effective prevention and treatment strategies. However, comprehensive global assessments of the disease burden of gastric cancer remain limited. This study, based on the Global Burden of Disease (GBD) framework, systematically analyzes global trends in gastric cancer from 1990 to 2021 and projects future trends through 2035, aiming to provide scientific evidence for policymaking.

Methods: The data were derived from the Global Burden of Disease (GBD) Study 2021, covering gastric cancer (GC) incidence, mortality, disability-adjusted life years (DALYs), age-standardized incidence rates (ASIRs), age-standardized death rates (ASDRs), and age-standardized DALY rates (ASRs) across 204 countries and regions from 1990 to 2021. The Bayesian age-period-cohort model was employed to project trends up to 2035.

Results: In comparison with 1990, both the incidence and mortality of GC rose in 2021, with over 1.23 million new cases recorded globally, resulting in 954,373.60 deaths and 22,786,633.10 DALYs. Between 1990 and 2021, the ASIRs, ASDRs, and ASRs decreased by 42% (ranging from 49 to 35%), 49% (ranging from 55 to 43%), and 53% (ranging from 58 to 47%), respectively. The peak ASIRs and ASDRs in 2021 were seen in the high-middle SDI quintile. Males exhibited higher rates of ASDRs, ASIRs, and ASRs compared to females. In 2021, East Asia and high-income North America bore the largest burden of smoking-related GC, while Central Europe experienced the highest burden from high-sodium diets. Forecasts toward 2035 indicate a continued decline in both ASIRs and ASDRs.

Conclusions: Despite notable reductions in both incidence and mortality, GC remains a substantial global burden, affecting various regions and countries. Deaths and DALYs related to high-sodium diets and smoking have shown an overall decline. However, substantial regional and age-related disparities persist. Targeted interventions, such as smoking control and promoting the intake of fresh fruits and vegetables, are essential in diminishing GC risk.

Although chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy against leukemic cells, it still has critical limitations. CAR macrophage has been regarded as a potential alternative to CAR T cells. However, due to the difficulties in gene transduction into macrophages, the production of primary human CAR macrophages from peripheral blood mononuclear cells (PBMC) using lentivirus is highly challenging. Here, we report on how to generate CAR macrophages from human PBMC with lentiviral particles. Using our lentiviral protocol, we produced functional CAR macrophages to lyse and phagocytose target cancer cells efficiently.

Background: Disease progression within 24 months (POD24) significantly impacts overall survival (OS) in patients with follicular lymphoma (FL). This study aimed to develop a robust predictive model, FLIPI-C, using a machine learning approach to identify FL patients at high risk of POD24.

Methods: A cohort of 1,938 FL patients (FL1-3a) from seventeen centers nationwide in China was randomly divided into training and internal validation sets (2:1 ratio). XGBoost was utilized to construct the POD24-predicting model, which was internally validated in the validation set and externally validated in the GALLIUM cohort. Key predictors of POD24 included lymphocyte-to-monocyte ratio (LMR), lactate dehydrogenase (LDH) > ULN, low hemoglobin (Hb), elevated beta-2 microglobulin (β2-MG), maximum standardized uptake value (SUVmax), and lymph node involvement. The FLIPI-C model assigned 2 points to LMR and 1 point to each of the other variables.

Results: The FLIPI-C model demonstrated superior accuracy (AUC) for predicting POD24 and 3-year overall survival (OS) in both the internal (AUC POD24: 0.764, OS: 0.700) and external validation cohorts (AUC POD24: 0.703, OS: 0.653), compared to existing models (FLIPI, FLIPI-2, PRIMA-PI, FLEX). Decision curve analysis confirmed the superior net benefits of FLIPI-C.

Conclusions: Developed using a machine learning approach, the FLIPI-C model offers superior predictive accuracy and utilizes simple, widely available markers. It holds promise for informing treatment decisions and prognostic assessments in clinical practice for FL patients at high risk of POD24.

The cathepsin family comprises lysosomal proteases that play essential roles in various physiological processes, including protein degradation, antigen presentation, apoptosis, and tissue remodeling. Dysregulation of cathepsin activity has been linked to a variety of pathological conditions, such as cancer, autoimmune diseases, and neurodegenerative disorders. Understanding the functions of cathepsins is crucial for gaining insights into their roles in both health and disease, as well as for developing targeted therapeutic approaches. Emerging research underscores the significant involvement of cathepsins in immune cells, particularly T cells, macrophages, dendritic cells, and neutrophils, as well as their contribution to immune-related diseases. In this review, we systematically examine the impact of cathepsins on the immune system and their mechanistic roles in cancer, infectious diseases, autoimmune and neurodegenerative disorders, with the goal of identifying novel therapeutic strategies for these conditions.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) was first reported in 2003 and confirmed to be strongly associated with familial hypercholesterolemia. Small-molecule inhibitors targeting PCSK9 provide an effective and safe method for managing hypercholesterolemia and reducing the cardiovascular risk. In recent years, increasing evidence has indicated other important roles for PCSK9 in inflammation, tumors, and even immune regulation. PCSK9 might be an attractive regulator of T-cell activation and expansion. It might mediate inflammation and regulate other types of immune cells. In this review, we summarize the current advances in the field of PCSK9 and provide a narrative of the biological processes associated with PCSK9. The relationships between PCSK9 and different T cells were investigated in depth. Finally, the signaling pathways associated with PCSK9 and the immune response are also summarized in this review.