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Frontiers in Immunology 2024Chimeric antigen receptor T (CAR-T) cell therapies have achieved remarkable success in the treatment of hematological tumors. However, given the distinct features of...
BACKGROUND
Chimeric antigen receptor T (CAR-T) cell therapies have achieved remarkable success in the treatment of hematological tumors. However, given the distinct features of solid tumors, particularly heterogeneity, metabolic aggressiveness, and fewer immune cells in tumor microenvironment (TME), the practical utility of CAR-T cells for solid tumors remains as a challenging issue. Meanwhile, although anti-PD-1 monoclonal antibody (mAb) has shown clinical efficacy, most mAbs also show limited clinical benefits for solid tumors due mainly to the issues associated with the lack of immune cells in TME. Thus, the infiltration of targeted immunological active cells into TME could generate synergistic efficacy for mAbs.
METHODS
We present a combinational strategy for solid tumor treatment, which combines armored-T cells to express Fc-gamma receptor I (FcγRI) fragment on the surfaces for targeting various tumors with therapeutically useful mAbs. Choosing CD20 and HER-2 as the targets, we characterized the and efficacy and latent mechanism of the combination drug by using flow cytometry, ELISA and other methods.
RESULTS
The combination and preprocessing of armored T-cells with corresponding antibody of Rituximab and Pertuzumab exerted profound anti-tumor effects, which is demonstrated to be mediated by synergistically produced antibody-dependent cellular cytotoxicity (ADCC) effects. Meanwhile, mAb was able to carry armored-T cell by preprocessing for the infiltration to TME in cell derived xenograft (CDX) model.
CONCLUSIONS
This combination strategy showed a significant increase of safety profiles from the reduction of antibody doses. More importantly, the present strategy could be a versatile tool for a broad spectrum of cancer treatment, with a simple pairing of engineered T cells and a conventional antibody.
Topics: Receptors, IgG; Humans; Animals; Mice; Neoplasms; T-Lymphocytes; Tumor Microenvironment; Antibodies, Monoclonal; Cell Line, Tumor; Xenograft Model Antitumor Assays; Immunotherapy, Adoptive; Receptor, ErbB-2; Antineoplastic Agents, Immunological; Receptors, Chimeric Antigen; Female; Antigens, CD20
PubMed: 38953027
DOI: 10.3389/fimmu.2024.1400177 -
Frontiers in Immunology 2024Antiglycine receptor (anti-GlyR) antibody mediates multiple immune-related diseases. This study aimed to summarize the clinical features to enhance our understanding of... (Review)
Review
BACKGROUND AND OBJECTIVES
Antiglycine receptor (anti-GlyR) antibody mediates multiple immune-related diseases. This study aimed to summarize the clinical features to enhance our understanding of anti-GlyR antibody-related disease.
METHODS
By collecting clinical information from admitted patients positive for glycine receptor (GlyR) antibody, the clinical characteristics of a new patient positive for GlyR antibody were reported in this study. To obtain additional information regarding anti-GlyR antibody-linked illness, clinical data and findings on both newly reported instances in this study and previously published cases were merged and analyzed.
RESULTS
A new case of anti-GlyR antibody-related progressive encephalomyelitis with rigidity and myoclonus (PERM) was identified in this study. A 20-year-old man with only positive cerebrospinal fluid anti-GlyR antibody had a good prognosis with first-line immunotherapy. The literature review indicated that the common clinical manifestations of anti-GlyR antibody-related disease included PERM or stiff-person syndrome (SPS) (n = 179, 50.1%), epileptic seizure (n = 94, 26.3%), and other neurological disorders (n = 84, 24.5%). Other neurological issues included demyelination, inflammation, cerebellar ataxia and movement disorders, encephalitis, acute psychosis, cognitive impairment or dementia, celiac disease, Parkinson's disease, neuropathic pain and allodynia, steroid-responsive deafness, hemiballism/tics, laryngeal dystonia, and generalized weakness included respiratory muscles. The group of PERM/SPS exhibited a better response to immunotherapy than others.
CONCLUSIONS
The findings suggest the presence of multiple clinical phenotypes in anti-GlyR antibody-related disease. Common clinical phenotypes include PERM, SPS, epileptic seizure, and paraneoplastic disease. Patients with RERM/SPS respond well to immunotherapy.
Topics: Humans; Male; Receptors, Glycine; Autoantibodies; Young Adult; Encephalomyelitis; Muscle Rigidity; Myoclonus; Stiff-Person Syndrome; Adult
PubMed: 38953026
DOI: 10.3389/fimmu.2024.1387591 -
Frontiers in Immunology 2024Anoikis is a form of programmed cell death essential for preventing cancer metastasis. In some solid cancer, anoikis resistance can facilitate tumor progression....
BACKGROUND
Anoikis is a form of programmed cell death essential for preventing cancer metastasis. In some solid cancer, anoikis resistance can facilitate tumor progression. However, this phenomenon is underexplored in clear-cell renal cell carcinoma (ccRCC).
METHODS
Using SVM machine learning, we identified core anoikis-related genes (ARGs) from ccRCC patient transcriptomic data. A LASSO Cox regression model stratified patients into risk groups, informing a prognostic model. GSVA and ssGSEA assessed immune infiltration, and single-cell analysis examined ARG expression across immune cells. Quantitative PCR and immunohistochemistry validated ARG expression differences between immune therapy responders and non-responders in ccRCC.
RESULTS
ARGs such as CCND1, CDKN3, PLK1, and BID were key in predicting ccRCC outcomes, linking higher risk with increased Treg infiltration and reduced M1 macrophage presence, indicating an immunosuppressive environment facilitated by anoikis resistance. Single-cell insights showed ARG enrichment in Tregs and dendritic cells, affecting immune checkpoints. Immunohistochemical analysis reveals that ARGs protein expression is markedly elevated in ccRCC tissues responsive to immunotherapy.
CONCLUSION
This study establishes a novel anoikis resistance gene signature that predicts survival and immunotherapy response in ccRCC, suggesting that manipulating the immune environment through these ARGs could improve therapeutic strategies and prognostication in ccRCC.
Topics: Humans; Carcinoma, Renal Cell; Anoikis; Kidney Neoplasms; Single-Cell Analysis; Prognosis; Gene Expression Regulation, Neoplastic; Drug Resistance, Neoplasm; Tumor Microenvironment; Lymphocytes, Tumor-Infiltrating; Transcriptome; Cell Line, Tumor; Biomarkers, Tumor; T-Lymphocytes, Regulatory; Gene Expression Profiling; Male; Multiomics
PubMed: 38953023
DOI: 10.3389/fimmu.2024.1427475 -
Frontiers in Immunology 2024Mast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide...
OBJECTIVES
Mast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide (SO) is an important regulator of MC function. However, the mechanism underlying its role in MC degranulation remains unclear. This study aimed to investigate the mechanism by which endogenous SO controlled MC degranulation.
METHODS
HMC-1 and Rat basophilic leukemia cell MC line (RBL-2H3) were used in the cell experiments. SO content was detected by fluorescent probe. MC degranulation represented by the release rate of MC β-hexosaminidase was determined using a colorimetric assay. Sulfenylation of galectin-9 (Gal-9) in MCs and purified protein was detected using a biotin switch assay. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the exact sulfenylation sites of Gal-9 by SO. Animal models of passive cutaneous anaphylaxis (PCA) and hypoxia-driven pulmonary vascular remodeling were used to investigate the effect of SO on mast cell activation . Site-directed mutation of Gal-9 was conducted to confirm the exact site of SO and support the significance of SO/Gal-9 signal axis in the regulation of MC degranulation.
RESULTS
Degranulation was increased in AAT1-knockdowned MCs, and SO supplementation reversed the increase in MC degranulation. Furthermore, deficiency of endogenous SO contributed to IgE-mediated degranulation Besides, SO inhibited IgE-mediated and hypoxia-driven MC degranulation . Mechanistically, LC-MS/MS analysis and site-directed mutation results showed that SO sulfenylated Gal-9 at cysteine 74. Sulfenylation of the 74 cysteine of Gal-9 protein was required in the SO-inhibited MC degranulation under both physiological and pathophysiological conditions.
CONCLUSION
These findings elucidated that SO inhibited MC degranulation via sulfenylating Gal-9 under both physiological and pathophysiological conditions, which might provide a novel treatment approach for MC activation-related diseases.
Topics: Animals; Cell Degranulation; Mast Cells; Cysteine; Rats; Sulfur Dioxide; Humans; Galectins; Mice; Male; Passive Cutaneous Anaphylaxis; Cell Line
PubMed: 38953022
DOI: 10.3389/fimmu.2024.1369326 -
Frontiers in Immunology 2024P2X receptors are a family of homo- and heterotrimeric cation channels gated by extracellular ATP. The P2X4 and P2X7 subunits show overlapping expression patterns and...
INTRODUCTION
P2X receptors are a family of homo- and heterotrimeric cation channels gated by extracellular ATP. The P2X4 and P2X7 subunits show overlapping expression patterns and have been involved in similar physiological processes, such as pain and inflammation as well as various immune cell functions. While formation of P2X2/P2X3 heterotrimers produces a distinct pharmacological phenotype and has been well established, functional identification of a P2X4/P2X7 heteromer has been difficult and evidence for and against a physical association has been found. Most of this evidence stems, however, from model systems.
METHODS
Here, we used a P2X7-EGFP BAC transgenic mouse model as well as P2X4 and P2X7 knock-out mice to re-investigate a P2X4-P2X7 interaction in mouse lung by biochemical and immunohistochemical experiments as well as quantitative expression analysis.
RESULTS
No detectable amounts of P2X4 could be co-purified from mouse lung via P2X7-EGFP. In agreement with these findings, immuno-histochemical analysis using a P2X7-specific nanobody revealed only limited overlap in the cellular and subcellular localizations of P2X4 and P2X7 in both the native lung tissue and primary cells. Comparison of P2X4 and P2X7 transcript and protein levels in the respective gene-deficient and wild type mice showed no mutual interrelation between their expression levels in whole lungs. However, a significantly reduced expression was found in alveolar macrophages of mice.
DISCUSSION
In summary, our detailed analysis of the cellular and subcellular P2X4 and P2X7 localization and expression does not support a physiologically relevant direct association of P2X4 and P2X7 subunits or receptors .
Topics: Animals; Receptors, Purinergic P2X4; Receptors, Purinergic P2X7; Mice; Lung; Mice, Knockout; Mice, Transgenic; Mice, Inbred C57BL; Protein Binding
PubMed: 38953020
DOI: 10.3389/fimmu.2024.1425938 -
Pathology Oncology Research : POR 2024Lung cancer is a leading cause of cancer-related death worldwide in both men and women, however mortality in the US and EU are recently declining in parallel with the... (Review)
Review
Lung cancer is a leading cause of cancer-related death worldwide in both men and women, however mortality in the US and EU are recently declining in parallel with the gradual cut of smoking prevalence. Consequently, the relative frequency of adenocarcinoma increased while that of squamous and small cell carcinomas declined. During the last two decades a plethora of targeted drug therapies have appeared for the treatment of metastasizing non-small cell lung carcinomas (NSCLC). Personalized oncology aims to precisely match patients to treatments with the highest potential of success. Extensive research is done to introduce biomarkers which can predict the effectiveness of a specific targeted therapeutic approach. The EGFR signaling pathway includes several sufficient targets for the treatment of human cancers including NSCLC. Lung adenocarcinoma may harbor both activating and resistance mutations of the EGFR gene, and further, mutations of KRAS and BRAF oncogenes. Less frequent but targetable genetic alterations include ALK, ROS1, RET gene rearrangements, and various alterations of MET proto-oncogene. In addition, the importance of anti-tumor immunity and of tumor microenvironment has become evident recently. Accumulation of mutations generally trigger tumor specific immune defense, but immune protection may be upregulated as an aggressive feature. The blockade of immune checkpoints results in potential reactivation of tumor cell killing and induces significant tumor regression in various tumor types, such as lung carcinoma. Therapeutic responses to anti PD1-PD-L1 treatment may correlate with the expression of PD-L1 by tumor cells. Due to the wide range of diagnostic and predictive features in lung cancer a plenty of tests are required from a single small biopsy or cytology specimen, which is challenged by major issues of sample quantity and quality. Thus, the efficacy of biomarker testing should be warranted by standardized policy and optimal material usage. In this review we aim to discuss major targeted therapy-related biomarkers in NSCLC and testing possibilities comprehensively.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Biomarkers, Tumor; Proto-Oncogene Mas
PubMed: 38953007
DOI: 10.3389/pore.2024.1611733 -
PeerJ 2024Cervical cancer remains a prevalent cancer among women, and reliance on surgical and radio-chemical therapies can irreversibly affect patients' life span and quality of...
BACKGROUND
Cervical cancer remains a prevalent cancer among women, and reliance on surgical and radio-chemical therapies can irreversibly affect patients' life span and quality of life. Thus, early diagnosis and further exploration into the pathogenesis of cervical cancer are crucial. Mass spectrometry technology is widely applied in clinical practice and can be used to further investigate the protein alterations during the onset of cervical cancer.
METHODS
Employing labeled-free quantitative proteomics technology and bioinformatics tools, we analyzed and compared the differential protein expression profiles between normal cervical squamous cell tissues and cervical squamous cell cancer tissues. GEPIA is an online website for analyzing the RNA sequencing expression data of tumor and normal tissue data from the TCGA and the GTEx databases. This approach aided in identifying qualitative and quantitative changes in key proteins related to the progression of cervical cancer.
RESULTS
Compared to normal samples, a total of 562 differentially expressed proteins were identified in cervical cancer samples, including 340 up-regulated and 222 down-regulated proteins. Gene ontology functional annotation, and KEGG pathway, and enrichment analysis revealed that the differentially expressed proteins mainly participated in metabolic pathways, spliceosomes, regulation of the actin cytoskeleton, and focal adhesion signaling pathways. Specifically, desmoplakin (DSP), protein phosphatase 1, regulatory (inhibitor) subunit 13 like (PPP1R13L) and ANXA8 may be involved in cervical tumorigenesis by inhibiting apoptotic signal transmission. Moreover, we used GEPIA database to validate the expression of DSP, PPP1R13L and ANXA8 in human cancers and normal cervix.
CONCLUSION
In this study, we identified 562 differentially expressed proteins, and there were three proteins expressed higher in the cervical cancer tissues. The functions and signaling pathways of these differentially expressed proteins lay a theoretical foundation for elucidating the molecular mechanisms of cervical cancer.
Topics: Humans; Female; Uterine Cervical Neoplasms; Proteomics; Carcinoma, Squamous Cell; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Computational Biology
PubMed: 38952985
DOI: 10.7717/peerj.17444 -
PeerJ 2024Ovarian cancer is an aggressive malignancy with high mortality known for its considerable metastatic potential. This study aimed to explore the expression and functional...
BACKGROUND
Ovarian cancer is an aggressive malignancy with high mortality known for its considerable metastatic potential. This study aimed to explore the expression and functional role of Unc-51 like autophagy activating kinase 2 (ULK2) in the progression of ovarian cancer.
METHODS
ULK2 expression patterns in ovarian cancer tissues as well as benign tumor control samples obtained from our institution were evaluated using immunohistochemistry. Cell counting kit 8 and Transwell assays were applied to assess the effects of ULK2 overexpression on cell proliferation, migration and invasion, respectively. RNA sequencing was performed to explore potential mechanisms of action of ULK2 beyond its classical autophagy modulation.
RESULTS
Our experiments showed significant downregulation of ULK2 in ovarian cancer tissues. Importantly, low expression of ULK2 was markedly correlated with decreased overall survival. functional studies further demonstrated that overexpression of ULK2 significantly suppressed tumor cell proliferation, migration, and invasion. RNA sequencing analysis revealed a potential regulatory role of ULK2 in the insulin signaling pathway through upregulation of insulin-like growth factor binding protein-3 (IGFBP3) in ovarian cancer cells.
CONCLUSIONS
In summary, the collective data indicated that ULK2 acted as a tumor suppressor in ovarian cancer by upregulating the expression of IGFBP3. Our study underscores the potential utility of ULK2 as a valuable prognostic marker for ovarian cancer.
Topics: Humans; Female; Cell Movement; Ovarian Neoplasms; Cell Line, Tumor; Neoplasm Invasiveness; Cell Proliferation; Insulin-Like Growth Factor Binding Protein 3; Autophagy-Related Protein-1 Homolog; Gene Expression Regulation, Neoplastic; Up-Regulation; Signal Transduction; Protein Serine-Threonine Kinases
PubMed: 38952983
DOI: 10.7717/peerj.17628 -
PeerJ 2024Andrographolide (Andro), an extract of (Burm.f.) Wall. ex Nees (Acanthaceae), possesses diverse biologically active properties. However, the precise mechanisms and...
BACKGROUND
Andrographolide (Andro), an extract of (Burm.f.) Wall. ex Nees (Acanthaceae), possesses diverse biologically active properties. However, the precise mechanisms and effects of Andro on pancreatic cancer (PC) remain unclear.
METHODS
The cytotoxic potential of Andro and underlying mechanism towards PC cells was investigated through experiments and a xenograft mouse model. PC cells were first subjected to varying concentrations of Andro. The reactive oxygen species (ROS) was assessed using flow cytometry and DCFH-DA staining. The apoptosis rate was detected by flow cytometry. Additionally, western blot was applied to evaluate the expression levels of cleaved-caspase-3, DJ-1, LC3-I, LC3-II, and p62. To further elucidate the involvement of ROS accumulation and autophagy, we employed N-acetylcysteine as a scavenger of ROS and 3-Methyladenine as an inhibitor of autophagy.
RESULTS
Andro demonstrated potent anti-proliferative effects on PC cells and induced apoptosis, both and . The cytotoxicity of Andro on PC cells was counteracted by DJ-1 overexpression. The reduction in DJ-1 expression caused by Andro led to ROS accumulation, subsequently inhibiting the growth of PC cells. Furthermore, Andro stimulated cytoprotective autophagy, thus weakening the antitumor effect. Pharmacological blockade of autophagy further enhanced the antitumor efficacy of Andro.
CONCLUSION
Our study indicated that ROS accumulation induced by the DJ-1 reduction played a key role in Andro-mediated PC cell inhibition. Furthermore, the protective autophagy induced by the Andro in PC cells is a mechanism that needs to be addressed in future studies.
Topics: Reactive Oxygen Species; Diterpenes; Pancreatic Neoplasms; Autophagy; Protein Deglycase DJ-1; Animals; Humans; Mice; Cell Line, Tumor; Apoptosis; Xenograft Model Antitumor Assays; Mice, Nude
PubMed: 38952980
DOI: 10.7717/peerj.17619 -
PeerJ 2024FAR1/FHY3 transcription factors are derived from transposase, which play important roles in light signal transduction, growth and development, and response to stress by...
BACKGROUND
FAR1/FHY3 transcription factors are derived from transposase, which play important roles in light signal transduction, growth and development, and response to stress by regulating downstream gene expression. Although many FAR1/FHY3 members have been identified in various species, the genes in maize are not well characterized and their function in drought are unknown.
METHOD
The FAR1/FHY3 family in the maize genome was identified using PlantTFDB, Pfam, Smart, and NCBI-CDD websites. In order to investigate the evolution and functions of FAR1 genes in maize, the information of protein sequences, chromosome localization, subcellular localization, conserved motifs, evolutionary relationships and tissue expression patterns were analyzed by bioinformatics, and the expression patterns under drought stress were detected by quantitative real-time polymerase chain reaction (qRT-PCR).
RESULTS
A total of 24 ZmFAR members in maize genome, which can be divided into five subfamilies, with large differences in protein and gene structures among subfamilies. The promoter regions of contain abundant abiotic stress-responsive and hormone-respovensive -elements. Among them, drought-responsive -elements are quite abundant. were expressed in all tissues detected, but the expression level varies widely. The expression of were mostly down-regulated in primary roots, seminal roots, lateral roots, and mesocotyls under water deficit. Most were down-regulated in root after PEG-simulated drought stress.
CONCLUSIONS
We performed a genome-wide and systematic identification of genes in maize. And most were down-regulated in root after drought stress. These results indicate that FAR1/FHY3 transcription factors have important roles in drought stress response, which can lay a foundation for further analysis of the functions of in response to drought stress.
Topics: Zea mays; Droughts; Gene Expression Regulation, Plant; Plant Proteins; Stress, Physiological; Transcription Factors
PubMed: 38952979
DOI: 10.7717/peerj.17684