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Journal For Immunotherapy of Cancer May 2024Cytokines are small proteins that regulate the growth and functional activity of immune cells, and several have been approved for cancer therapy. Oncolytic viruses are... (Review)
Review
Cytokines are small proteins that regulate the growth and functional activity of immune cells, and several have been approved for cancer therapy. Oncolytic viruses are agents that mediate antitumor activity by directly killing tumor cells and inducing immune responses. Talimogene laherparepvec is an oncolytic herpes simplex virus type 1 (oHSV), approved for the treatment of recurrent melanoma, and the virus encodes the human cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF). A significant advantage of oncolytic viruses is the ability to deliver therapeutic payloads to the tumor site that can help drive antitumor immunity. While cytokines are especially interesting as payloads, the optimal cytokine(s) used in oncolytic viruses remains controversial. In this review, we highlight preliminary data with several cytokines and chemokines, including GM-CSF, interleukin 12, FMS-like tyrosine kinase 3 ligand, tumor necrosis factor α, interleukin 2, interleukin 15, interleukin 18, chemokine (C-C motif) ligand 2, chemokine (C-C motif) ligand 5, chemokine (C-X-C motif) ligand 4, or their combinations, and show how these payloads can further enhance the antitumor immunity of oHSV. A better understanding of cytokine delivery by oHSV can help improve clinical benefit from oncolytic virus immunotherapy in patients with cancer.
Topics: Humans; Oncolytic Virotherapy; Oncolytic Viruses; Cytokines; Immunotherapy; Neoplasms; Animals; Simplexvirus; Herpesvirus 1, Human
PubMed: 38821716
DOI: 10.1136/jitc-2023-008025 -
World Journal of Hepatology May 2024In this editorial we comment on the review by Zhou reviewing the landscape of nanomedicine in the treatment of hepatocellular carcinoma (HCC). We focus on the immense...
In this editorial we comment on the review by Zhou reviewing the landscape of nanomedicine in the treatment of hepatocellular carcinoma (HCC). We focus on the immense potential of nanotechnology, particularly ligand-receptor mediated nanotherapy, in revolutionizing the treatment landscape of HCC. Despite advancements in multidisciplinary treatment, HCC remains a significant global health challenge. Ligand-mediated nanotherapy offers the opportunity for precise drug delivery to tumor sites, targeting specific receptors overexpressed in HCC cells, thereby enhancing efficacy and minimizing side effects. Overcoming drug resistance and aggressive tumor biology is facilitated by nanomedicine, bypassing traditional hurdles encountered in chemotherapy. Examples include targeting glypican-3, asialoglycoprotein, transferrin receptor or folic acid receptors, capitalizing on their over-expression in tumor cells. The ability for multi-receptor targeting through dual-ligand nanoparticle modification holds the prospect of further enhancement in specificity and efficacy of directed therapy. However, challenges including immune responses, reproducibility in nanoparticle synthesis, and production scalability remain. Future directions involve refining targeting strategies, improving drug release mechanisms, and streamlining production processes to enable personalized and multifunctional nanotherapies. Overall, the integration of nanotherapy in HCC treatment holds immense promise, but continued partnership and effort are needed in offering hope for more effective, precise, and accessible clinical care in the management of HCC.
PubMed: 38818296
DOI: 10.4254/wjh.v16.i5.684 -
Journal of Cancer 2024To explore the hub gene closely related to the progression of gastric cancer (GC), so as to provide a theoretical basis for revealing the therapeutic mechanism of GC....
To explore the hub gene closely related to the progression of gastric cancer (GC), so as to provide a theoretical basis for revealing the therapeutic mechanism of GC. The gene expression profile and clinical data of GSE15459 in Gene Expression Omnibus (GEO) database were downloaded. The weighted gene co-expression network analysis (WGCNA) was used to screen the key modules related to GC progression. Survival analysis was used to assess the influence of hub genes on patients' outcomes. CIBERSORT analysis was used to predict the tissue infiltrating immune cells in patients. Immunohistochemical staining was conducted to further verify the expression of hub genes. Through WGCNA, a total of 26 co-expression modules were constructed, in which salmon module and royalblue module had strong correlation with GC progression. The results of enrichment analysis showed that genes in the two modules were mainly involved in toll-like receptor signaling pathway, cholesterol metabolism and neuroactive ligand-receptor interaction. Six hub genes (, , , , and ) related to GC progression were screened. Survival analysis showed overall survival in the high expression group was significantly lower than that in the low expression group. CIBERSORT analysis revealed that immune characteristics difference between patients in early stage and advanced stage. Immunohistochemical results confirmed that , , and were significantly associated with disease progression in GC. Our study identified that , , and played important roles in the progression of GC, and their specific mechanisms are worth further study.
PubMed: 38817876
DOI: 10.7150/jca.95757 -
Journal of Cancer 2024Chemoresistance is a key reason for treatment failure in colorectal cancer (CRC) patients. The tumor microenvironment of chemoresistant CRC is distinctly...
Chemoresistance is a key reason for treatment failure in colorectal cancer (CRC) patients. The tumor microenvironment of chemoresistant CRC is distinctly immunosuppressive, although the underlying mechanisms are unclear. The CRC data sets GSE69657 and GSE62080 were downloaded from the GEO database, and the correlation between TRPC5 and FAP expression was analyzed by Pearson method. The in-situ expression of transient receptor potential channel 5 (TRPC5) and fibroblast activation protein (FAP) in the CRC tissues was examined by immunohistochemistry. TRPC5 expression levels in the HCT8 and HCT116 cell lines and the corresponding 5-fluorouracil (5-FU)-resistant cell lines (HCT8R and HCT116R) were analyzed by western blotting and RT-PCR. Exosomes were isolated from the HCT8R and HCT116R cells and incubated with colorectal normal fibroblasts (NFs), and cancer-associated fibroblasts (CAFs)markers were detected. NFs were also incubated with exosomes isolated from TRPC5-knockdown HCT8R cells, and the changes in intracellular Ca levels and C-X-C motif chemokine ligand 12 (CXCL12) secretion were analyzed. TRPC5 and FAP expression showed positive correlation in the datasets. Immunostaining of CRC tissue specimens further revealed that high TRPC5 and FAP expressions were significantly associated with worse tumor regression. Furthermore, chemoresistant CRC cells expressed higher levels of TRPC5 compared to the chemosensitive cells, and knocking down TRPC5 reversed chemoresistance. Exosomes derived from CRC cells induced the transformation of NFs to CAFs. However, TRPC5-exosomes derived from chemoresistant CRC cells can promote CAFs to secrete more CXCL12. Chemoresistant CRC cells can induce CAFs activation and promote CXCL12 secretion through exosomal TRPC5.
PubMed: 38817851
DOI: 10.7150/jca.95248 -
World Journal of Gastrointestinal... May 2024Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare type of non-small-cell lung cancer. Stomach lymphoepithelioma-like carcinoma (LELC) metastasis secondary to...
BACKGROUND
Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare type of non-small-cell lung cancer. Stomach lymphoepithelioma-like carcinoma (LELC) metastasis secondary to PLELC has not been reported recently.
CASE SUMMARY
A 64-year-old female was admitted to our hospital for a regular gastroscopy examination with a 6-year history of surgical resection for left PLELC. Positron emission tomography/computed tomography suggested high accumulation of 18F-fludeoxyglucose in the gastric cardia region. Upper gastrointestinal endoscopy confirmed a large mass at the stomach fundus. Immunohistochemistry (IHC) of the biopsy suggested metastatic stomach LELC. Proximal gastrectomy showed that this 6.5 cm × 5.0 cm mass was located in the stomach fundus near the cardia. Histopathological examination showed a poorly differentiated carcinoma with prominent lymphoplasmacytic infiltration. IHC demonstrated that the tumor was positive for CK (AE1/AE3), p63, p40, p53, Ki-67 (70%), and EGFR (3+) and negative for CK7, CK20, Her2, and CD10. hybridization analysis showed positive staining Epstein-Barr virus-encoded RNA. Tumor programmed cell death ligand 1 (PD-L1) expression score was 98%, and the combined positive score was 100, with no evidence of microsatellite instability. Thus, the patient was unequivocally diagnosed with metastatic stomach LELC secondary to pulmonary LELC. After discharge, this patient underwent PD-1 inhibitor treatment (toripalimab, 240 mg) every 3 wk for ten cycles, and she has had no tumor recurrence.
CONCLUSION
For gastric LELC metastasis, PD-1 inhibitor therapy could become a new therapeutic approach, though there is still no evidence from large data sets to support this.
PubMed: 38817283
DOI: 10.4240/wjgs.v16.i5.1436 -
Journal For Immunotherapy of Cancer May 2024The incidence of papillary thyroid cancer (PTC) continues to rise all over the world, 10-15% of the patients have a poor prognosis. Although immunotherapy has been...
BACKGROUND
The incidence of papillary thyroid cancer (PTC) continues to rise all over the world, 10-15% of the patients have a poor prognosis. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation of the mechanism of PTC immune remodeling and exploration of novel treatment targets.
METHODS
This study conducted a single-cell RNA sequencing (scRNA-seq) analysis using 18 surgical tissue specimens procured from 14 patients diagnosed with adjacent tissues, non-progressive PTC or progressive PTC. Key findings were authenticated through spatial transcriptomics RNA sequencing, immunohistochemistry, multiplex immunohistochemistry, and an independent bulk RNA-seq data set containing 502 samples.
RESULTS
A total of 151,238 individual cells derived from 18 adjacent tissues, non-progressive PTC and progressive PTC specimens underwent scRNA-seq analysis. We found that progressive PTC exhibits the following characteristics: a significant decrease in overall immune cells, enhanced immune evasion of tumor cells, and disrupted antigen presentation function. Moreover, we identified a subpopulation of lysosomal associated membrane protein 3 (LAMP3) dendritic cells (DCs) exhibiting heightened infiltration in progressive PTC and associated with advanced T stage and poor prognosis of PTC. LAMP3 DCs promote CD8 T cells exhaustion (mediated by NECTIN2-TIGIT) and increase infiltration abundance of regulatory T cells (mediated by chemokine (C-C motif) ligand 17 (CCL17)-chemokine (C-C motif) receptor 4 (CCR4)) establishing an immune-suppressive microenvironment. Ultimately, we unveiled that progressive PTC tumor cells facilitate the retention of LAMP3 DCs within the tumor microenvironment through NECTIN3-NECTIN2 interactions, thereby rendering tumor cells more susceptible to immune evasion.
CONCLUSION
Our findings expound valuable insights into the role of the interaction between LAMP3 DCs and T-cell subpopulations and offer new and effective ideas and strategies for immunotherapy in patients with progressive PTC.
Topics: Humans; Dendritic Cells; Thyroid Cancer, Papillary; Lysosomal-Associated Membrane Protein 3; Thyroid Neoplasms; Male; Female; Tumor Microenvironment; Middle Aged; Tumor Escape; T-Lymphocyte Subsets; Neoplasm Proteins
PubMed: 38816233
DOI: 10.1136/jitc-2024-008983 -
Journal of Medical Genetics May 2024Variants in underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to...
BACKGROUND AND AIMS
Variants in underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism.
METHODS
knockout ( ) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients. knockout and knockdown retinal pigment epithelial-1 cells and mouse embryonic fibroblasts were generated to study cell division and cell death.
RESULTS
The mice were normal overall, particularly with respect to hepatobiliary features. However, when challenged with α-naphthyl isothiocyanate, mice developed changes resembling those in ZFYVE19-deficient patients, including elevated serum liver injury markers, increased numbers of bile duct profiles with abnormal cholangiocyte polarity and biliary fibrosis. Failure of cell division, centriole and cilia abnormalities, and increased cell death were observed in knockdown/knockout cells. Increased cell death and altered mRNA expression of cell death-related signalling pathways was demonstrated in livers from mice and patients. Transforming growth factor-β (TGF-β) and Janus kinase-Signal Transducer and Activator of Transcription 3 (JAK-STAT3) signalling pathways were upregulated in vivo, as were chemokines such as C-X-C motif ligands 1, 10 and 12.
CONCLUSIONS
Our findings demonstrated that ZFYVE19 deficiency is a ciliopathy with novel histological features. Failure of cell division with ciliary abnormalities and cell death activates macrophages and may thus lead to biliary fibrosis via TGF-β pathway in the disease.
PubMed: 38816193
DOI: 10.1136/jmg-2023-109779 -
PLoS Genetics May 2024Whether single-cell RNA-sequencing (scRNA-seq) captures the same biological information as single-nucleus RNA-sequencing (snRNA-seq) remains uncertain and likely to be...
Whether single-cell RNA-sequencing (scRNA-seq) captures the same biological information as single-nucleus RNA-sequencing (snRNA-seq) remains uncertain and likely to be context-dependent. Herein, a head-to-head comparison was performed in matched normal-adenocarcinoma human lung samples to assess biological insights derived from scRNA-seq versus snRNA-seq and better understand the cellular transition that occurs from normal to tumoral tissue. Here, the transcriptome of 160,621 cells/nuclei was obtained. In non-tumor lung, cell type proportions varied widely between scRNA-seq and snRNA-seq with a predominance of immune cells in the former (81.5%) and epithelial cells (69.9%) in the later. Similar results were observed in adenocarcinomas, in addition to an overall increase in cell type heterogeneity and a greater prevalence of copy number variants in cells of epithelial origin, which suggests malignant assignment. The cell type transition that occurs from normal lung tissue to adenocarcinoma was not always concordant whether cells or nuclei were examined. As expected, large differential expression of the whole-cell and nuclear transcriptome was observed, but cell-type specific changes of paired normal and tumor lung samples revealed a set of common genes in the cells and nuclei involved in cancer-related pathways. In addition, we showed that the ligand-receptor interactome landscape of lung adenocarcinoma was largely different whether cells or nuclei were evaluated. Immune cell depletion in fresh specimens partly mitigated the difference in cell type composition observed between cells and nuclei. However, the extra manipulations affected cell viability and amplified the transcriptional signatures associated with stress responses. In conclusion, research applications focussing on mapping the immune landscape of lung adenocarcinoma benefit from scRNA-seq in fresh samples, whereas snRNA-seq of frozen samples provide a low-cost alternative to profile more epithelial and cancer cells, and yield cell type proportions that more closely match tissue content.
PubMed: 38814983
DOI: 10.1371/journal.pgen.1011301 -
Heliyon May 2024In metal-organic frameworks (MOFs), confined space as a chemical nanoreactor is as essential as coordinatively unsaturated metal site catalysis. The properties of MOFs...
In metal-organic frameworks (MOFs), confined space as a chemical nanoreactor is as essential as coordinatively unsaturated metal site catalysis. The properties of MOFs can be adjusted through the incorporation of functional groups and open metal sites in frameworks that can modify the catalytic performance. In this regard, a set of defect-engineered MOFs, Ex-MOF-808(NH, NO, H) and Mix-MOF-808(NH, NO, H), were synthesized by ultrasonic-assisted linker exchange approach (Ex-MOFs) and solvothermal mixing ligand method (Mix-MOFs), respectively. Further, the relationship between the preparation method, structural properties, and catalytic efficiency of the prepared materials in the selective oxidation of methyl phenyl sulfide (MPS) has been investigated. By analyzing zeta potential, it was found that in the exchange method, the amount of defect and functional groups on the surface of MOFs are more than in the mixing method, which also affects the catalytic activity. In our contribution, mix-MOF-808(NO) carrying nitro groups at their organic linkers, which has a well-dispersion of nitro groups at the framework exhibits selective conversion of MPS to sulfone (91 %). Furthermore, the performance of stable heterogeneous catalysts was investigated for three cycles, which demonstrated their great potential for advanced catalytic oxidation.
PubMed: 38813201
DOI: 10.1016/j.heliyon.2024.e31254 -
Brain, Behavior, & Immunity - Health Jul 2024The nerve growth factor receptor, also referred to as tumour necrosis factor II and the p75 neurotrophin receptor (p75), serves pleiotropic functions in both the...
The nerve growth factor receptor, also referred to as tumour necrosis factor II and the p75 neurotrophin receptor (p75), serves pleiotropic functions in both the peripheral and central nervous system, involving modulation of immune responses, cell survival and cell death signalling in response to multiple ligands including cytokines such as TNFα, as well as proneurotrophins and mature neurotrophins. Whilst and studies have characterised various responses of the p75 receptor in isolated conditions, it remains unclear whether the p75 receptor serves to provide neuroprotection or contributes to neurotoxicity in neuroinflammatory and neurotrophin-deficit conditions, such as those presenting in schizophrenia. The purpose of this mini-review is to characterise the potential signalling mechanisms of the p75 receptor respective to neuropathological changes prevailing in schizophrenia to ultimately propose how specific functions of the receptor may underlie altered levels of p75 in specific cell types. On the basis of this evaluation, this mini-review aims to promote avenues for future research in utilising the therapeutic potential of ligands for the p75 receptor in psychiatric disorders, whereby heightened inflammation and reductions in trophic signalling mechanisms coalesce in the brain, potentially resulting in tissue damage.
PubMed: 38813083
DOI: 10.1016/j.bbih.2024.100796