scholarly journals Advances in Hypofractionated Irradiation-Induced Immunosuppression of Tumor Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuxia Wang
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Hypofractionated Radiotherapy ◽  
Enhancement Effect ◽  
Beam Irradiation ◽  
Antitumor Effects ◽  
External Beam Irradiation ◽  
Innate And Adaptive Immunity ◽  
Higher Doses ◽  
Hypofractionated Irradiation

Hypofractionated radiotherapy is external beam irradiation delivered at higher doses in fewer fractions than conventional standard radiotherapy, which can stimulate innate and adaptive immunity to enhance the body’s immune response against cancer. The enhancement effect of hypofractionated irradiation to immune response has been widely investigated, which is considered an approach to expand the benefit of immunotherapy. Meanwhile, increasing evidence suggests that hypofractionated irradiation may induce or enhance the suppression of immune microenvironments. However, the suppressive effects of hypofractionated irradiation on immunomicroenvironment and the molecular mechanisms involved in these conditions are largely unknown. In this context, we summarized the immune mechanisms associated with hypofractionated irradiation, highlighted the advances in its immunosuppressive effect, and further discussed the potential mechanism behind this effect. In our opinion, besides its immunogenic activity, hypofractionated irradiation also triggers homeostatic immunosuppressive mechanisms that may counterbalance antitumor effects. And this may suggest that a combination with immunotherapy could possibly improve the curative potential of hypofractionated radiotherapy.

scholarly journals The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Kanzaki ◽  
Tetsuhiro Chiba ◽  
Junjie Ao ◽  
Keisuke Koroki ◽  
Kengo Kanayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Erk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antitumor Effects ◽  
The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

scholarly journals Modulation of the Immune Response by Deferasirox in Myelodysplastic Syndrome Patients

2021 ◽  
Vol 14 (1) ◽  
pp. 41
Author(s):  
Hana Votavova ◽  
Zuzana Urbanova ◽  
David Kundrat ◽  
Michaela Dostalova Merkerova ◽  
Martin Vostry ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Blood Cell ◽  
Myelodysplastic Syndrome ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Adaptive Immune Response ◽  
Gene Expression Profiles ◽  
Iron Chelator ◽  
Multiple Cancer

Deferasirox (DFX) is an oral iron chelator used to reduce iron overload (IO) caused by frequent blood cell transfusions in anemic myelodysplastic syndrome (MDS) patients. To study the molecular mechanisms by which DFX improves outcome in MDS, we analyzed the global gene expression in untreated MDS patients and those who were given DFX treatment. The gene expression profiles of bone marrow CD34+ cells were assessed by whole-genome microarrays. Initially, differentially expressed genes (DEGs) were determined between patients with normal ferritin levels and those with IO to address the effect of excessive iron on cellular pathways. These DEGs were annotated to Gene Ontology terms associated with cell cycle, apoptosis, adaptive immune response and protein folding and were enriched in cancer-related pathways. The deregulation of multiple cancer pathways in iron-overloaded patients suggests that IO is a cofactor favoring the progression of MDS. The DEGs between patients with IO and those treated with DFX were involved predominantly in biological processes related to the immune response and inflammation. These data indicate DFX modulates the immune response mainly via neutrophil-related genes. Suppression of negative regulators of blood cell differentiation essential for cell maturation and upregulation of heme metabolism observed in DFX-treated patients may contribute to the hematopoietic improvement.

scholarly journals A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/β-catenin signaling pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Wei Xie ◽  
Huijie Zhao ◽  
Fengxian Wang ◽  
Yiyun Wang ◽  
Yuan He ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Near Infrared ◽  
Triple Negative ◽  
Vasculogenic Mimicry ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Antitumor Effects ◽  
Mouse Xenograft Model

Abstract Background Anti-angiogenic therapy has been widely applied to the clinical treatment of malignant tumors. However, the efficacy of such treatments has been called into question, especially in triple-negative breast cancer (TNBC). Bevacizumab, the first anti-angiogenic agent approved by FDA, actually increases invasive and metastatic properties of TNBC cells, resulting from the activation of Wnt/β-catenin signaling in response to hypoxia. As a critical receptor of Wnt/β-catenin signaling, Frizzled-7 (Fzd7) is aberrantly expressed in TNBC, indicating Fzd7 a potential target for developing drugs to be combined with anti-angiogenic agents. Methods Hybridoma technique and antibody humanization technique were utilized to generate a Fzd7-targeting antibody (SHH002-hu1). Biolayer interferometry (BLI) assay and near infrared (NIR) imaging were conducted to detect the affinity and targeting ability of SHH002-hu1. Next, whether SHH002-hu1 could suppress the invasion and migration of TNBC cells induced by Bevacizumab were validated, and the underlying molecular mechanisms were elucidated by luciferase reporter and western blot assays. The nude-mice transplanted TNBC models were established to assess the anti-TNBC activities of SHH002-hu1 when combined with Bevacizumab. Then, the effects on putative TNBC stem-like cells and Wnt/β-catenin signaling were evaluated by immunofluorescence (IF). Further, the tumor-initiating and self-renew capacity of TNBC cells were studied by secondary nude mouse xenograft model and sphere formation assay. In addition, the effects of SHH002-hu1 on the adaptation of TNBC cells to hypoxia were evaluated by the detection of vasculogenic mimicry (VM) and hypoxia-inducible factor-1α (HIF-1α) transcriptional activity. Results The novel humanized antibody targeting Fzd7 (SHH002-hu1) exhibited extremely high affinity with Fzd7, and specifically targeted to Fzd7+ cells and tumor tissues. SHH002-hu1 repressed invasion, migration and epithelial-mesenchymal cell transformation (EMT) of TNBC cells induced by Bevacizumab through abating Wnt/β-catenin signaling. SHH002-hu1 significantly enhanced the capacity of Bevacizumab to inhibit the growth of TNBC via reducing the subpopulation of putative TNBC stem-like cells, further attenuating Bevacizumab-enhanced tumor-initiating and self-renew capacity of TNBC cells. Moreover, SHH002-hu1 effectively restrained the adaptation of TNBC cells to hypoxia via disrupting Wnt/β-catenin signaling. Conclusion SHH002-hu1 significantly enhances the anti-TNBC capacity of Bevacizumab, and shows the potential of preventing TNBC recurrence, suggesting SHH002-hu1 a good candidate for the synergistic therapy together with Bevacizumab.

scholarly journals TAMI-07. THE IMMUNE MICROENVIRONMENT IN LOWER GRADE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii214-ii214
Author(s):  
Anupam Kumar ◽  
Katharine Chen ◽  
Claudia Petritsch ◽  
Theodore Nicolaides ◽  
Mariarita Santi-Vicini ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
T Regulatory Cells ◽  
Immune Cell ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Lower Grade ◽  
Functional Relationships

Abstract The determinants of the tumor-associated immune response in brain tumors are poorly understood. Using tumor samples from two molecularly distinct subtypes of lower grade glioma, MAPK-driven glioma with biallelic inactivation of CDKN2A (n=30) and IDH-mutant, 1p/19q-intact astrocytoma (n=29), we demonstrate qualitative and quantitative differences in the tumor-associated immune response and we investigate the molecular mechanisms involved. Histologically the MAPK-driven gliomas were comprised of pleomorphic xanthoastrocytoma (PXA) (n=11) and anaplastic PXA (n=19). Seven patients had paired samples from two sequential surgeries. Immune cell populations and their activity were determined by quantitative multiplex immunostaining and Digital Spatial Profiling and gene expression was analyzed by Nanostring. Functional studies were performed using established cell lines and two new patient-derived lines from MAPK-driven LGGs. MAPK-driven tumors exhibited an increased number of CD8+ T cells and tumor-associated microglial/macrophage (TAMs), including CD163+ TAMs, as compared to IDH-mutant astrocytoma. In contrast, IDH-mutant tumors had increased FOXP3+ immunosuppressive T regulatory cells. Transcriptional and protein level analyses in MAPK-driven tumors suggested an active cytotoxic T cell response with robust expression of granzyme B, present on 27% of CD8+ T cells, increased MHC class I expression, and altered cytokine profiles. Interestingly, MAPK-driven tumors also had increased expression of immunosuppressive molecules, including CXCR4, PD-L1, and VEGFA. Expression differences for cell surface and secreted proteins were confirmed in patient-derived tumor lines and functional relationships between altered chemokine expression and immune cell infiltration was investigated. Our data provide novel insights into the immune contexture of MAPK driven LGGs and suggest MAPK driven gliomas with biallelic inactivation of CDKN2A may be particularly vulnerable to immunotherapeutic modulation

scholarly journals Beneficial Actions of Orostachys japonica and Its Compounds against Tumors via MAPK Signaling Pathways

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 555
Author(s):  
Soyoung Hur ◽  
Eungyeong Jang ◽  
Jang-Hoon Lee
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Malignant Tumors ◽  
Treatment Options ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Perennial Plant

Tumors are one of the most life-threatening diseases, and a variety of cancer treatment options have been continuously introduced in order to overcome cancer and improve conventional therapy. Orostachys japonica (O. japonica), which is a perennial plant belonging to the genus Orostachys of the Crassulaceae family, has been revealed to exhibit pharmacological properties against various tumors in numerous studies. The present review aimed to discuss the biological actions and underlying molecular mechanisms of O. japonica and its representative compounds—kaempferol and quercetin—against tumors. O. japonica reportedly has antiproliferative, anti-angiogenic, and antimetastatic activities against various types of malignant tumors through the induction of apoptosis and cell cycle arrest, a blockade of downstream vascular endothelial growth factor (VEGF)-VEGFR2 pathways, and the regulation of epithelial-to-mesenchymal transition. In addition, emerging studies have highlighted the antitumor efficacy of kaempferol and quercetin. Interestingly, it was found that alterations of the mitogen-activated protein kinase (MAPK) signaling cascades are involved in the pivotal mechanisms of the antitumor effects of O. japonica and its two compounds against cancer cell overgrowth, angiogenesis, and metastasis. In summary, O. japonica could be considered a preventive and therapeutic medicinal plant which exhibits antitumor actions by reversing altered patterns of MAPK cascades, and kaempferol and quercetin might be potential components that can contribute to the efficacy and underlying mechanism of O. japonica.

scholarly journals TRIM31 facilitates K27-linked polyubiquitination of SYK to regulate antifungal immunity

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xueer Wang ◽  
Honghai Zhang ◽  
Zhugui Shao ◽  
Wanxin Zhuang ◽  
Chao Sui ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Fungal Pathogen ◽  
Essential Role ◽  
Molecular Mechanisms ◽  
Systemic Infection ◽  
Lectin Receptors ◽  
Innate And Adaptive Immunity ◽  
Cytokines And Chemokines

AbstractSpleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase, which plays an essential role in both innate and adaptive immunity. However, the key molecular mechanisms that regulate SYK activity are poorly understood. Here we identified the E3 ligase TRIM31 as a crucial regulator of SYK activation. We found that TRIM31 interacted with SYK and catalyzed K27-linked polyubiquitination at Lys375 and Lys517 of SYK. This K27-linked polyubiquitination of SYK promoted its plasma membrane translocation and binding with the C-type lectin receptors (CLRs), and also prevented the interaction with the phosphatase SHP-1. Therefore, deficiency of Trim31 in bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) dampened SYK-mediated signaling and inhibited the secretion of proinflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection. Trim31−/− mice were also more sensitive to C. albicans systemic infection than Trim31+/+ mice and exhibited reduced Th1 and Th17 responses. Overall, our study uncovered the pivotal role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and highlighted the significance of TRIM31 in anti-C. albicans immunity.

scholarly journals Integrated Insight into the Molecular Mechanisms of Spontaneous Abortion during Early Pregnancy in Pigs

2021 ◽  
Vol 22 (12) ◽  
pp. 6644
Author(s):  
Xupeng Zang ◽  
Ting Gu ◽  
Wenjing Wang ◽  
Chen Zhou ◽  
Yue Ding ◽  
...  
Keyword(s):  
Immune Response ◽  
Spontaneous Abortion ◽  
Molecular Mechanisms ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Gene Set ◽  
Cerna Network ◽  
Major Interest ◽  
End Stage ◽  
Insight Into

Due to the high rate of spontaneous abortion (SAB) in porcine pregnancy, there is a major interest and concern on commercial pig farming worldwide. Whereas the perturbed immune response at the maternal–fetal interface is an important mechanism associated with the spontaneous embryo loss in the early stages of implantation in porcine, data on the specific regulatory mechanism of the SAB at the end stage of the implantation remains scant. Therefore, we used high-throughput sequencing and bioinformatics tools to analyze the healthy and arresting endometrium on day 28 of pregnancy. We identified 639 differentially expressed lncRNAs (DELs) and 2357 differentially expressed genes (DEGs) at the end stage of implantation, and qRT-PCR was used to verify the sequencing data. Gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immunohistochemistry analysis demonstrated weaker immune response activities in the arresting endometrium compared to the healthy one. Using the lasso regression analysis, we screened the DELs and constructed an immunological competitive endogenous RNA (ceRNA) network related to SAB, including 4 lncRNAs, 11 miRNAs, and 13 genes. In addition, Blast analysis showed the applicability of the constructed ceRNA network in different species, and subsequently determined HOXA-AS2 in pigs. Our study, for the first time, demonstrated that the SAB events at the end stages of implantation is associated with the regulation of immunobiological processes, and a specific molecular regulatory network was obtained. These novel findings may provide new insight into the possibility of increasing the litter size of sows, making pig breeding better and thus improving the efficiency of animal husbandry production.

scholarly journals Transcriptome Analysis of the Cecal Tonsil of Jingxing Yellow Chickens Revealed the Mechanism of Differential Resistance to Salmonella

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 979 ◽  
Author(s):  
Fei Wang ◽  
Jin Zhang ◽  
Bo Zhu ◽  
Jie Wang ◽  
Qiao Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
Pathogenic Bacteria ◽  
Molecular Mechanisms ◽  
Differential Resistance ◽  
Receptor Interaction ◽  
Salmonella Infection ◽  
Poultry Products ◽  
Food Borne ◽  
Cecal Tonsil ◽  
Iga Production

Salmonella is one of the most common food-borne pathogens. It can be transmitted between chickens, as well as to people by contaminated poultry products. In our study, we distinguished chickens with different resistances mainly based on bacterial loads. We compared the cecal tonsil transcriptomes between the susceptible and resistant chickens after Salmonella infection, aiming to identify the crucial genes participating in the antibacterial activity in the cecal tonsil. A total of 3214 differentially expressed genes (DEGs), including 2092 upregulated and 1122 downregulated genes, were identified between the two groups (fold change ≥ 2.0, padj < 0.05). Many DEGs were mainly involved in the regulation of two biological processes: crosstalk between the cecal tonsil epithelium and pathogenic bacteria, such as focal adhesion, extracellular-matrix–receptor interaction, and regulation of the actin cytoskeleton and host immune response including the cytokine–receptor interaction. In particular, the challenged resistant birds exhibited strong activation of the intestinal immune network for IgA production, which perhaps contributed to the resistance to Salmonella infection. These findings give insight into the mRNA profile of the cecal tonsil between the two groups after initial Salmonella stimulation, which may extend the known complexity of molecular mechanisms in chicken immune response to Salmonella.

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