Synthetic Matrix Scaffolds Engineer the in Vivo Tumor Immune Microenvironment for Immunotherapy Screening

2022 ◽  
pp. 2108084
Author(s):  
Meghan J. O'Melia ◽  
Adriana Mulero‐Russe ◽  
Jihoon Kim ◽  
Alyssa Pybus ◽  
Deborah DeRyckere ◽  
...  
Keyword(s):  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Synthetic Matrix

scholarly journals Development and validation of genomic and epigenomic signatures associated with tumor immune microenvironment in hepatoblastoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yanbing Zhang ◽  
Tian Zhang ◽  
Qiang Yin ◽  
Haiyan Luo
Keyword(s):  
Immune Cells ◽  
Hepg2 Cells ◽  
Migration And Invasion ◽  
Immune Microenvironment ◽  
Hub Genes ◽  
Normal Tissues ◽  
Tumor Immune Microenvironment ◽  
Sample Correlation ◽  
Development And Validation

Abstract Background This study aimed to probe and verify aberrantly methylated and expressed genes in hepatoblastoma and to analyze their interactions with tumor immune microenvironment. Methods Aberrantly methylated and expressed genes were obtained by comprehensively analyzing gene expression and DNA methylation profiles from GSE81928, GSE75271 and GSE78732 datasets. Their biological functions were predicted by the STRING and Metascape databases. CIBERSORT was utilized for inferring the compositions of tumor-infiltrating immune cells (TIICs) in each sample. Correlation between hub genes and immune cells was then analyzed. Hub genes were validated in hepatoblastoma tissues via western blot or immunohistochemistry. After transfection with sh-NOTUM, migration and invasion of HuH-6 and HepG2 cells were investigated. The nude mouse tumorigenesis model was constructed. Results Totally, 83 aberrantly methylated and expressed genes were determined in hepatoblastoma, which were mainly involved in metabolic and cancer-related pathways. Moreover, their expression was liver-specific. 13 hub genes were screened, which were closely related to immune cells in hepatoblastoma tissues. Among them, it was confirmed that AXIN2, LAMB1 and NOTUM were up-regulated and SERPINC1 was down-regulated in hepatoblastoma than normal tissues. NOTUM knockdown distinctly weakened migration and invasion of HuH-6 and HepG2 cells and tumor growth in vivo. Conclusions This study identified aberrantly methylated and expressed signatures that were in relation to immune microenvironment in hepatoblastoma. Targeting NOTUM hub gene could suppress migration and invasion of hepatoblastoma cells. Thus, these aberrantly methylated and expressed genes might act as therapeutic agents in hepatoblastoma therapy.

scholarly journals Dopamine Pathway Mediated by DRD5 Facilitates Tumor Growth via Enhancing Warburg Effect in Esophageal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaozhe Qian ◽  
Donglei Zhang ◽  
Ziang Cao ◽  
Haitao Ma
Keyword(s):  
Esophageal Cancer ◽  
Tumor Cells ◽  
Lymphatic Metastasis ◽  
Warburg Effect ◽  
Transcriptional Analysis ◽  
Immune Microenvironment ◽  
Tumor Tissues ◽  
Tumor Immune Microenvironment

Esophageal cancer (EC) is among the most malignant cancers globally due to its aggressiveness and poor survival. To set off from the inflammatory tumor immune microenvironment, we analyzed tumor tissues of EC patients with or without lymphatic metastasis to explore the importance of cancer cell derived neurotransmitters. Results have emphasized that the accumulation of dopamine but not other neurotransmitters could be observed in EC tumor tissue of patients, especially those who are bearing lymphatic metastasis. Transcriptional analysis of mentioned tissues was also performed to filter out key enzymes involved in dopamine pathway including tyrosine hydroxylase (TH), DOPA decarboxylase (DCC), monoamine oxidase (MAO), etc. Further analysis on tumor tissues of patients indicated that dopamine receptor D5 was aberrantly upregulated and co-located with TH. Both in vitro and in vivo tests have demonstrated that dopamine could stimulate the proliferation and outgrowth of EC tumor cells via the DRD5 mediated pathway. The exploration of mechanism has unveiled that activation of the dopamine pathway significantly enhanced the uptake of glucose and production of lactate of EC tumor cells. It can also facilitate the extracellular acid rate (ECAR), dedicating that DRD5-mediated activated dopamine pathway could effectively form and trigger Warburg effect, which is modulated by the cross-talk of mTOR and AKT pathway. Our results would unveil the relationship between cancer derived neurotransmitters and inflammatory tumor immune microenvironment, thus provide potential therapeutic targets and novel clinical strategy towards metastatic EC.

scholarly journals Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer

2020 ◽  
Vol 6 (20) ◽  
pp. eaba1590 ◽  
Author(s):  
Xue Dong ◽  
Pei Pan ◽  
Di-Wei Zheng ◽  
Peng Bao ◽  
Xuan Zeng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
In Vivo Studies ◽  
Host Immune System ◽  
Immune Microenvironment ◽  
Phage Display Technology ◽  
Tumor Immune Microenvironment

Mounting evidence suggests that the gut microbiota contribute to colorectal cancer (CRC) tumorigenesis, in which the symbiotic Fusobacterium nucleatum (Fn) selectively increases immunosuppressive myeloid-derived suppressor cells (MDSCs) to hamper the host’s anticancer immune response. Here, a specifically Fn-binding M13 phage was screened by phage display technology. Then, silver nanoparticles (AgNP) were assembled electrostatically on its surface capsid protein (M13@Ag) to achieve specific clearance of Fn and remodel the tumor-immune microenvironment. Both in vitro and in vivo studies showed that of M13@Ag treatment could scavenge Fn in gut and lead to reduction in MDSC amplification in the tumor site. In addition, antigen-presenting cells (APCs) were activated by M13 phages to further awaken the host immune system for CRC suppression. M13@Ag combined with immune checkpoint inhibitors (α-PD1) or chemotherapeutics (FOLFIRI) significantly prolonged overall mouse survival in the orthotopic CRC model.

706 BT7480, a fully synthetic tumor-targeted immune cell agonist (TICA™) induces tumor localized CD137 agonism and modulation of tumor immune microenvironment

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A748-A748
Author(s):  
Punit Upadhyaya ◽  
Kristen Hurov ◽  
Jessica Kublin ◽  
Jun Ma ◽  
Elizabeth Repash ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Immune Microenvironment ◽  
Plasma Exposure ◽  
Tumor Models ◽  
Human Pbmc ◽  
Tumor Immune Microenvironment ◽  
Animal Care ◽  
Anti Tumor Activity

BackgroundAfter disappointing first clinical experiences with agonistic anti-CD137 (4-1BB) antibodies, a new generation of both systemic and targeted CD137 agonists is entering clinical development.1–3 These strategies rely on biologic agents with suboptimal properties for CD137 agonism due to their relatively large sizes and long circulating half-lives. These properties may limit their tissue penetration and cause sustained agonism resulting in overstimulation and activation-induced cell death of lymphocytes due to continuous exposure.Fully synthetic constrained bicyclic peptides (Bicycles™) with antibody-like affinities and target selectivity are uniquely suited to circumvent the above barriers to optimal targeted CD137 agonistic therapeutics. BT7480 is a tumor-targeted immune cell agonist (TICA) designed to deliver a highly potent CD137 agonist to Nectin-4 overexpressing tumor tissue with a flexible dosing schedule maximizing anti-tumor activity while circumventing the need for continuous systemic exposure.MethodsBT7480 functional activity in vitro was analyzed by measuring IL-2 and IFN gamma production from primary human PBMC/tumor cell co-cultures. BT7480 in vivo activity was determined in huCD137-syngeneic tumor models using tumor immune cell and transcriptional profiling by FACS, IHC, and Nanostring as well as tumor growth kinetics as read-outs.ResultsBT7480 binds potently and simultaneously to Nectin-4 and CD137 as assessed biochemically and caused Nectin-4-dependent CD137 agonism in primary human PBMC co-cultured with tumor cells. Treatment of Nectin-4 expressing tumors in immunocompetent mice with BT7480 leads to profound reprogramming of the tumor immune microenvironment including increased T cell infiltration and upregulation of a cytotoxic cell gene signature. BT7480 treatment induces complete tumor regressions and subsequent resistance to tumor re-challenge. TICA-dependent anti-tumor activity and established immunologic memory are dependent on cytotoxic T cells. Importantly, BT7480 in vivo activity is not dependent on continuous plasma exposure since once weekly dosing of BT7480 provides a maximum anti-tumor activity despite minimal BT7480 plasma exposure after day 2.BT7480 demonstrates linear pharmacokinetics in non-human primates and appears well tolerated at exposures in excess of the predicted efficacious exposure in humans.ConclusionsBT7480 is a highly potent Nectin-4 expression dependent CD137 agonist with optimal target binding, pharmacologic, and pharmacokinetic properties that enable intermittent dosing for curative effect through modulation of tumor immune microenvironment in syngeneic mouse tumor models. BT7480 is currently being evaluated in IND-enabling safety studies.Ethics ApprovalThe care and use of animals were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of WuXi AppTec and conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).ReferencesHinner, et al. Tumor-localized costimulatory t-cell engagement by the 4-1BB/HER2 Bispecific antibody-anticalin fusion PRS-343. Clin. Cancer Res 2019 Oct 1;25(19):5878–5889.Claus, et al. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Sci. Transl. Med 2019 Jun 12;11(496):eaav5989.Eskiocak, et al. Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity. JCI Insight 2020 Mar 12;5(5):e133647.

scholarly journals Screening of tumor microenvironment-related prognostic genes in breast cancer by data mining

2020 ◽  
Author(s):  
Yunhui LI ◽  
Na REN
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
B Cells ◽  
Memory T Cells ◽  
Immune Therapy ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Immune Score

Abstract Background Accumulating evidence has demonstrated that the components of tumor immune microenvironment (TME) play important roles in breast cancer (BC) initiation, progression and prognosis. Materials and methods We downloaded the TCGA, GSE12276, GSE58812 and GSE42568 datasets. We calculated the immune scores and tumor immune infiltrating cells (TIICs) of TCGA-BRCA and GEO datasets using ESTIMATE and CIBERSORT algorithm, respectively. Then, the overlapping immune-related differentially expressed genes (DEGs) were screened using R ‘limma ’ package between TCGA and GSE12276 datasets. The GO and KEGG enrichment analysis were used to predict the function and signaling pathways of common DEGs. Finally, we extracted a series of tumor immune microenvironment-related genes, and explore the relationship between these genes and clinical outcomes in TCGA, GSE58812 and GSE42568 datasets. Results Based on the ESTIMATE algorithm, the immune scores were significantly associated with cancer types, as well as overall survival in BC patients. The fractions of some TIICs, such asnaïve B cells, memory B cells, CD8 + T cells, resting CD4 + memory T cells, activated CD4 + memory T cells, resting NK cells, monocytes, macrophage M0, M1, M2, resting DCs, activated DCs and resting mast cells, were significantly different between low and high immune score groups (all P <0.05). The DEGs between low and high immune score groups were mainly involved in immune-related biological processes, including adaptive immune response, innate response and inflammatory response. Finally, we found that ACSL5, GIMAP2, HLA-DRA and CLEC10A were significantly associated with prognosis among TCGA, GASE58812 and GSE42568 datasets (all P <0.05). Conclusion These findings provide a more comprehensive understanding of immune cells and immune-related genes within TME as well as prognosis-related genes in BC. Future studies need to perform in vivo and in vitro experiments to clarify the mechanisms of these genes in TME and provide a comprehensive idea to immune therapy.

scholarly journals miR-24-3p/KLF8 Signaling Axis Contributes to LUAD Metastasis by Regulating EMT

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Pengyu Jing ◽  
Nianlin Xie ◽  
Nan Zhao ◽  
Ximing Zhu ◽  
Pei Li ◽  
...  
Keyword(s):  
Salient Feature ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Activity Assay ◽  
Immune Microenvironment ◽  
Therapeutic Value ◽  
Tumor Immune Microenvironment ◽  
Signaling Axis

Reprogramming of the tumor immune microenvironment is a salient feature during metastasis in LUAD. miR-24-3p and KLF8, which are key regulators of the tumor immune microenvironment, had been proved to show metastasis-promoting property in LUAD. However, whether miR-24-3p could regulate LUAD metastasis by targeting KLF8 remains unclear. This study explored the functions and mechanisms of miR-24-3p/KLF8 signaling in advanced LUAD. The expression level of miR-24-3p and KLF8 were tested in LUAD patients, and the corelation of miR-24-3p and KLF8 was evaluated. The interaction of miR-24-3p and KLF8 was demonstrated by luciferase reporter activity assay, in vitro migration and invasion studies, and in vivo metastatic studies. miR-24-3p level was downregulated in LUAD and negatively associated with KLF8 mRNA expression. miR-24-3p controls LUAD metastasis by directly targeting KLF8 and inducing Snail and E-cadherin expressions. Targeting the miR-24-3p/KLF8/EMT axis might be of great therapeutic value to advanced LUAD patients.

scholarly journals Phenotyping the tumor-immune microenvironment (TiME) in vivo by cellular-level optical imaging reveals unique combination phenotypes with variable inflammation and endothelial anergy

2021 ◽  
Author(s):  
Aditi Sahu ◽  
Teguru Tembo ◽  
Kivanc Kose ◽  
Anthony Santella ◽  
Anabel Alfonso ◽  
...  
Keyword(s):  
Optical Imaging ◽  
Tumor Immunity ◽  
Immune Checkpoint Blockade ◽  
Cellular Level ◽  
Added Value ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Clinical Benefits ◽  
Relative Prevalence

Immunotherapies, especially immune checkpoint blockade therapy have shown unprecedented clinical benefits in several malignancies, however, responses are variable emphasizing the need for effective biomarkers for patient stratification1. Phenotyping of tumors into hot, altered, or cold2 based on T-lymphocyte infiltration in tumor biopsies fails to explain and/or predict response to immunotherapy seen in a subset of patients3,4. One of the primary reasons for this suboptimal prediction by a single immune marker could be attributed to the fact that additional mechanisms within the tumor microenvironment modulate anti-tumor immunity and outcomes, including dynamic events such as tumor-angiogenesis and leukocyte trafficking2,5,6. We report novel tumor phenotypes through non-invasive spatially-resolved cellular-level analysis of the tumor immune microenvironment (TiME) and major determinants of anti-tumor immunity. Using skin cancers as a model and optical imaging using reflectance confocal microscopy (RCM)7, we determined four major phenotypes based on unsupervised clustering for relative prevalence of vasculature (Vasc) and inflammation (Inf) features: VaschighInfhigh, VaschighInflow, VasclowInf(intratumoral)high and VascmodInflow. The VaschighInfhigh phenotype correlate with high immune and vascular signatures while VaschighInflow with endothelial anergy. Automated quantification of TiME features demonstrates moderate accuracy and high correlation with corresponding gene expression. Prospective testing of TiME features prior to topical immunotherapy response shows highest response in the VasclowInf(IT)high phenotype, and revealing the added value of vascular features in predicting treatment response. This novel in vivo phenotyping combining dynamic immune and vascular features has the potential to advance fundamental understanding of the highly dynamic TiME, identify novel druggable pathways and develop robust predictors for immunotherapy outcomes.

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