scholarly journals Tissues and Tumor Microenvironment (TME) in 3D: Models to Shed Light on Immunosuppression in Cancer

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 831
Author(s):  
Teresa Ho ◽  
Rasha Msallam
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Cell ◽  
3D Models ◽  
Genetic Alterations ◽  
Experimental Models ◽  
Model Systems ◽  
Patient Specific ◽  
Great Promise ◽  
The Impact

Immunosuppression in cancer has emerged as a major hurdle to immunotherapy efforts. Immunosuppression can arise from oncogene-induced signaling within the tumor as well as from tumor-associated immune cells. Understanding various mechanisms by which the tumor can undermine and evade therapy is critical in improving current cancer immunotherapies. While mouse models have allowed for the characterization of key immune cell types and their role in tumor development, extrapolating these mechanisms to patients has been challenging. There is need for better models to unravel the effects of genetic alterations inherent in tumor cells and immune cells isolated from tumors on tumor growth and to investigate the feasibility of immunotherapy. Three-dimensional (3D) organoid model systems have developed rapidly over the past few years and allow for incorporation of components of the tumor microenvironment such as immune cells and the stroma. This bears great promise for derivation of patient-specific models in a dish for understanding and determining the impact on personalized immunotherapy. In this review, we will highlight the significance of current experimental models employed in the study of tumor immunosuppression and evaluate current tumor organoid-immune cell co-culture systems and their potential impact in shedding light on cancer immunosuppression.

scholarly journals When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Katrin Schlie ◽  
Jaeline E. Spowart ◽  
Luke R. K. Hughson ◽  
Katelin N. Townsend ◽  
Julian J. Lum
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Patient Treatment ◽  
Low Oxygen ◽  
Tumor Environment ◽  
And Function ◽  
The Impact

Hypoxia is a signature feature of growing tumors. This cellular state creates an inhospitable condition that impedes the growth and function of all cells within the immediate and surrounding tumor microenvironment. To adapt to hypoxia, cells activate autophagy and undergo a metabolic shift increasing the cellular dependency on anaerobic metabolism. Autophagy upregulation in cancer cells liberates nutrients, decreases the buildup of reactive oxygen species, and aids in the clearance of misfolded proteins. Together, these features impart a survival advantage for cancer cells in the tumor microenvironment. This observation has led to intense research efforts focused on developing autophagy-modulating drugs for cancer patient treatment. However, other cells that infiltrate the tumor environment such as immune cells also encounter hypoxia likely resulting in hypoxia-induced autophagy. In light of the fact that autophagy is crucial for immune cell proliferation as well as their effector functions such as antigen presentation and T cell-mediated killing of tumor cells, anticancer treatment strategies based on autophagy modulation will need to consider the impact of autophagy on the immune system.

scholarly journals 492 Integration of high dimensional datasets in an immunocompetent mammary mouse model reveals pathways of tolerance and resistance to immune checkpoint blockade

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A528-A528
Author(s):  
Lin Ma ◽  
Jian-Hua Mao ◽  
Mary Helen Barcellos-Hoff ◽  
Jade Moore
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Systemic Disease ◽  
Ct Imaging ◽  
High Dimensional ◽  
Cytokine Signaling ◽  
Immune Infiltrate ◽  
Pet Ct

BackgroundCheckpoint inhibitors can induce robust and durable responses in a subset of patients. Extending this benefit to more patients could be facilitated by better understanding of how interacts with immune cells with the tumor microenvironment, which is a critical barrier to control both local and systemic disease. The composition and pattern of the immune infiltrate associates with the likelihood of response to immunotherapy. Inflamed tumors that exhibit a brisk immune cell infiltrate are responsive, while those in which immune cells are completely or partially excluded are not. Transforming growth factor β (TGFβ) is immunosuppressive and associated with the immune excluded phenotype.MethodsUsing an immune competent mammary tumor derived transplant (mTDT) model recently developed in our lab, exhibits inflamed, excluded or deserts immune infiltrate phenotypes based on localization of CD8 lymphocytes. Using whole transcriptome deep sequencing, cytof, and PET-CT imaging, we evaluated the tumor, microenvironment, and immune pathway activation among immune infiltrate phenotypes.ResultsThree distinct inflamed tumors phenotypes were identified: ‘classically’ inflamed characterized by pathway evidence of increased CD8+ T cells and decreased PD-L1 expression, inflamed tumors with pathways indicative of neovascularization and STAT3 signaling and reduced T cell mobilization, and an inflamed tumor with increased immunosuppressive myeloid phenotypes. Excluded tumors were characterized by TGFβ gene expression and pro-inflammatory cytokine signaling (e.g. TNFα, IL1β), associated with decreased leukocytes homing and increased immune cell death of cells. We visualized and quantified TGFβ activity using PET-CT imaging of 89Zr-fresolimumab, a TGFβ neutralizing antibody. TGFβ activity was significantly increased in excluded tumors compared to inflamed or desert tumors, which was supported by quantitative pathology (Perkin Elmer) of its canonical signaling target, phosphorylated SMAD2 (pSMAD2). pSMAD2 was positively correlated with PD-L1 expression in the stroma of excluded tumors. In contrast, in inflamed tumors, TGFβ activity positively correlated with increased F4/80 positive macrophages and negatively correlated with expression of PD-L1. CyTOF analysis of tumor and spleen immune phenotypes revealed increased trafficking of myeloid cells in mice bearing inflamed tumors compared to excluded and deserts.ConclusionsThe immunocompetent mTDT provides a model that bridges the gap between the immune landscape and tumor microenvironment. Integration of these high-dimensional data with further studies of response to immunotherapies will help to identify tumor features that favor response to treatment or the means to convert those that are unresponsive.

scholarly journals Platelets, immune cells and the coagulation cascade; friend or foe of the circulating tumour cell?

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Mark P. Ward ◽  
Laura E. Kane ◽  
Lucy A. Norris ◽  
Bashir M. Mohamed ◽  
Tanya Kelly ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Circulatory System ◽  
Morphological Characteristics ◽  
Metastatic Potential ◽  
Coagulation Cascade ◽  
Molecular Profile ◽  
Great Promise ◽  
Liquid Biopsies

AbstractCancer cells that transit from primary tumours into the circulatory system are known as circulating tumour cells (CTCs). These cancer cells have unique phenotypic and genotypic characteristics which allow them to survive within the circulation, subsequently extravasate and metastasise. CTCs have emerged as a useful diagnostic tool using “liquid biopsies” to report on the metastatic potential of cancers. However, CTCs by their nature interact with components of the blood circulatory system on a constant basis, influencing both their physical and morphological characteristics as well as metastatic capabilities. These properties and the associated molecular profile may provide critical diagnostic and prognostic capabilities in the clinic. Platelets interact with CTCs within minutes of their dissemination and are crucial in the formation of the initial metastatic niche. Platelets and coagulation proteins also alter the fate of a CTC by influencing EMT, promoting pro-survival signalling and aiding in evading immune cell destruction. CTCs have the capacity to directly hijack immune cells and utilise them to aid in CTC metastatic seeding processes. The disruption of CTC clusters may also offer a strategy for the treatment of advance staged cancers. Therapeutic disruption of these heterotypical interactions as well as direct CTC targeting hold great promise, especially with the advent of new immunotherapies and personalised medicines. Understanding the molecular role that platelets, immune cells and the coagulation cascade play in CTC biology will allow us to identify and characterise the most clinically relevant CTCs from patients. This will subsequently advance the clinical utility of CTCs in cancer diagnosis/prognosis.

scholarly journals Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy

Oncogene ◽  
2021 ◽  
Author(s):  
Audrey Lequeux ◽  
Muhammad Zaeem Noman ◽  
Malina Xiao ◽  
Kris Van Moer ◽  
Meriem Hasmim ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Transcriptional Activity ◽  
Immune Cell ◽  
Tumor Resistance ◽  
Combination Strategy ◽  
Immune Effector ◽  
Effector Cells ◽  
Melanoma Patients ◽  
The Impact

AbstractHypoxia is a key factor responsible for the failure of therapeutic response in most solid tumors and promotes the acquisition of tumor resistance to various antitumor immune effectors. Reshaping the hypoxic immune suppressive tumor microenvironment to improve cancer immunotherapy is still a relevant challenge. We investigated the impact of inhibiting HIF-1α transcriptional activity on cytotoxic immune cell infiltration into B16-F10 melanoma. We showed that tumors expressing a deleted form of HIF-1α displayed increased levels of NK and CD8+ effector T cells in the tumor microenvironment, which was associated with high levels of CCL2 and CCL5 chemokines. We showed that combining acriflavine, reported as a pharmacological agent preventing HIF-1α/HIF-1β dimerization, dramatically improved the benefit of cancer immunotherapy based on TRP-2 peptide vaccination and anti-PD-1 blocking antibody. In melanoma patients, we revealed that tumors exhibiting high CCL5 are less hypoxic, and displayed high NK, CD3+, CD4+ and CD8+ T cell markers than those having low CCL5. In addition, melanoma patients with high CCL5 in their tumors survive better than those having low CCL5. This study provides the pre-clinical proof of concept for a novel triple combination strategy including blocking HIF-1α transcription activity along vaccination and PD-1 blocking immunotherapy.

scholarly journals In Vitro Evaluation of CD276-CAR NK-92 Functionality, Migration and Invasion Potential in the Presence of Immune Inhibitory Factors of the Tumor Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1020
Author(s):  
Stefan Grote ◽  
Guillermo Ureña-Bailén ◽  
Kenneth Chun-Ho Chan ◽  
Caroline Baden ◽  
Markus Mezger ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Immune Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Migration And Invasion ◽  
Cellular Immunotherapy ◽  
Knock Out ◽  
Immunosuppressive Tumor Microenvironment

Background: Melanoma is the most lethal of all skin-related cancers with incidences continuously rising. Novel therapeutic approaches are urgently needed, especially for the treatment of metastasizing or therapy-resistant melanoma. CAR-modified immune cells have shown excellent results in treating hematological malignancies and might represent a new treatment strategy for refractory melanoma. However, solid tumors pose some obstacles for cellular immunotherapy, including the identification of tumor-specific target antigens, insufficient homing and infiltration of immune cells as well as immune cell dysfunction in the immunosuppressive tumor microenvironment (TME). Methods: In order to investigate whether CAR NK cell-based immunotherapy can overcome the obstacles posed by the TME in melanoma, we generated CAR NK-92 cells targeting CD276 (B7-H3) which is abundantly expressed in solid tumors, including melanoma, and tested their effectivity in vitro in the presence of low pH, hypoxia and other known factors of the TME influencing anti-tumor responses. Moreover, the CRISPR/Cas9-induced disruption of the inhibitory receptor NKG2A was assessed for its potential enhancement of NK-92-mediated anti-tumor activity. Results: CD276-CAR NK-92 cells induced specific cytolysis of melanoma cell lines while being able to overcome a variety of the immunosuppressive effects normally exerted by the TME. NKG2A knock-out did not further improve CAR NK-92 cell-mediated cytotoxicity. Conclusions: The strong cytotoxic effect of a CD276-specific CAR in combination with an “off-the-shelf” NK-92 cell line not being impaired by some of the most prominent negative factors of the TME make CD276-CAR NK-92 cells a promising cellular product for the treatment of melanoma and beyond.

scholarly journals Experimental Models to Study COVID-19 Effect in Stem Cells

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 91
Author(s):  
Rishi Man Chugh ◽  
Payel Bhanja ◽  
Andrew Norris ◽  
Subhrajit Saha
Keyword(s):  
Stem Cells ◽  
Ex Vivo ◽  
Drug Efficacy ◽  
Cell Loss ◽  
Experimental Models ◽  
Model Systems ◽  
Virus Infectivity ◽  
Ex Vivo Model ◽  
Global Pandemic ◽  
The Impact

The new strain of coronavirus (severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)) emerged in 2019 and hence is often referred to as coronavirus disease 2019 (COVID-19). This disease causes hypoxic respiratory failure and acute respiratory distress syndrome (ARDS), and is considered as the cause of a global pandemic. Very limited reports in addition to ex vivo model systems are available to understand the mechanism of action of this virus, which can be used for testing of any drug efficacy against virus infectivity. COVID-19 induces tissue stem cell loss, resulting inhibition of epithelial repair followed by inflammatory fibrotic consequences. Development of clinically relevant models is important to examine the impact of the COVID-19 virus in tissue stem cells among different organs. In this review, we discuss ex vivo experimental models available to study the effect of COVID-19 on tissue stem cells.

scholarly journals Nutritional immunity: the impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Claire Healy ◽  
Natalia Munoz-Wolf ◽  
Janné Strydom ◽  
Lynne Faherty ◽  
Niamh C. Williams ◽  
...  
Keyword(s):  
Immune System ◽  
Trace Metals ◽  
Lung Disease ◽  
Chronic Lung Disease ◽  
Immune Cells ◽  
Immune Cell ◽  
Redox Activity ◽  
Nutritional Immunity ◽  
Airway Microbiome ◽  
The Impact

AbstractNutritional immunity is the sequestration of bioavailable trace metals such as iron, zinc and copper by the host to limit pathogenicity by invading microorganisms. As one of the most conserved activities of the innate immune system, limiting the availability of free trace metals by cells of the immune system serves not only to conceal these vital nutrients from invading bacteria but also operates to tightly regulate host immune cell responses and function. In the setting of chronic lung disease, the regulation of trace metals by the host is often disrupted, leading to the altered availability of these nutrients to commensal and invading opportunistic pathogenic microbes. Similarly, alterations in the uptake, secretion, turnover and redox activity of these vitally important metals has significant repercussions for immune cell function including the response to and resolution of infection. This review will discuss the intricate role of nutritional immunity in host immune cells of the lung and how changes in this fundamental process as a result of chronic lung disease may alter the airway microbiome, disease progression and the response to infection.

Identification of Immune-Related Prognostic Biomarkers in Pancreatic Cancer

2020 ◽  
Vol 12 (12) ◽  
pp. 1355-1367
Author(s):  
Xiaoyan Lin ◽  
Jiakang Ma ◽  
Kaikai Ren ◽  
Mingyu Hou ◽  
Bo Zhou ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Risk Score ◽  
Immune Cells ◽  
Immune Cell ◽  
Cox Regression ◽  
Individual Treatment ◽  
Survival Prediction ◽  
Lasso Regression ◽  
Immune Related Genes

Immunotherapy for pancreatic cancer (PC) faces significant challenges. It is urgent to find immunerelated genes for targeted therapy. We aimed to identify immune-related messenger ribonucleic acids (mRNAs) with multiple methods of comprehensive immunoenrichment analysis in predicting survival of PC. PC genomics and clinical data were downloaded from TCGA. We analyzed relative enrichment of 29 immune cells using ssGSEA and classified PC samples into three immuneinfiltrating subgroups. Immune cell infiltration level and pathways were evaluated by ESTIMATE data and KEGG. Independent risk factors were derived from the combined analysis of WGCNA, LASSO regression and Cox regression analyses. Immune risk score was calculated according to four mRNAs to identify its value in predicting survival. PPI analysis was used to analyze the connections and potential pathways among genes. Finally, PC samples were classified into three immuneinfiltrating subgroups. Immunity high subgroup had higher immune score, soakage of immune cells, HLA/PD-L1 expression level, immune-related pathways enrichment and better survivability. Four potential prognostic immune-related genes (ITGB7, RAC2, DNASE1L3, and TRAF1) were identified. Immune risk score could be a potential survival prediction indictor with high sensitivity and specificity (AUC values = 0.708, HR = 1.445). A PPI network with seven nodes and five potential targeted pathways were generated. In conclusion, we estimated the state of immune infiltration in the PC tumor microenvironment by calculating stromal and immune cells enrichment with ssGSEA algorithms, and identified four prognostic immune-related genes that affect the proportion and distribution of immune cells infiltration in the tumor microenvironment. They lay a theoretical foundation to be important immunity targets of individual treatment in PC.

scholarly journals Experimental Models of Brugada syndrome

2019 ◽  
Vol 20 (9) ◽  
pp. 2123 ◽  
Author(s):  
Sendfeld ◽  
Selga ◽  
Scornik ◽  
Pérez ◽  
Mills ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Experimental Models ◽  
Model Systems ◽  
Patient Specific ◽  
Canine Heart ◽  
Stem Cell Technology ◽  
St Segment Elevation ◽  
St Segment ◽  
Cardiac Sodium Channel ◽  
The Right

Brugada syndrome is an inherited, rare cardiac arrhythmogenic disease, associated with sudden cardiac death. It accounts for up to 20% of sudden deaths in patients without structural cardiac abnormalities. The majority of mutations involve the cardiac sodium channel gene SCN5A and give rise to classical abnormal electrocardiogram with ST segment elevation in the right precordial leads V1 to V3 and a predisposition to ventricular fibrillation. The pathophysiological mechanisms of Brugada syndrome have been investigated using model systems including transgenic mice, canine heart preparations, and expression systems to study different SCN5A mutations. These models have a number of limitations. The recent development of pluripotent stem cell technology creates an opportunity to study cardiomyocytes derived from patients and healthy individuals. To date, only a few studies have been done using Brugada syndrome patient-specific iPS-CM, which have provided novel insights into the mechanisms and pathophysiology of Brugada syndrome. This review provides an evaluation of the strengths and limitations of each of these model systems and summarizes the key mechanisms that have been identified to date.

scholarly journals Mitosis in Cancer Cell Increases Immune Resistance via High Expression of HLA-G and PD-L1

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2661
Author(s):  
Matti Ullah ◽  
Warda Aoudjeghout ◽  
Cynthia Pimpie ◽  
Marc Pocard ◽  
Massoud Mirshahi
Keyword(s):  
Protein Expression ◽  
Cancer Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
G1 Phase ◽  
G2 Phase ◽  
The Impact

Cancer is a result of “aggressive” division and uncontrolled proliferation of the abnormal cells that survive attack by immune cells. We investigated the expression of HLA-G and PD-L1 with the different stages of cancer cell division along with their role in the interaction of immune cells in vitro. Ovarian cancer (OVCAR-3) and chronic myeloid leukemia cell line (K-562) are used for this study. The correlation of protein expression with percentage of cells in each phase (G1, S and G2 phase) was evaluated through FACS. Cells were synchronized in G1, G2 and mitotic phase to evaluate gene (RT-qPCR) and protein expression (FACS). Real-time immune cell attack (RTICA) analysis with PBMCs (peripheral blood mono-nuclear cells) and cancer cells were performed. We found that cells expressing higher levels of HLA-G and PD-L1 are mainly in G2 phase and those expressing lower levels are mainly in G1 phase. Evidently, the higher expression of the two proteins was observed when synchronized in mitotic phase as compared to low expression when synchronized in G1 phase. RTICA analysis showed the presence of HLA-G delayed the lysis of the cells. In conclusion, the cancer cell can escape from immune cells in division stage that suggests the impact of mitosis index for cancer immunotherapy.

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