scholarly journals Metabolic Factors Affecting Tumor Immunogenicity: What Is Happening at the Cellular Level?

2021 ◽  
Vol 22 (4) ◽  
pp. 2142
Author(s):  
Rola El Sayed ◽  
Yolla Haibe ◽  
Ghid Amhaz ◽  
Youssef Bouferraa ◽  
Ali Shamseddine
Keyword(s):  
Fatty Acid ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Modulation ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Effector Memory ◽  
Acid Oxidation ◽  
Checkpoint Inhibition ◽  
Inflammatory Phenotypes

Immunotherapy has changed the treatment paradigm in multiple solid and hematologic malignancies. However, response remains limited in a significant number of cases, with tumors developing innate or acquired resistance to checkpoint inhibition. Certain “hot” or “immune-sensitive” tumors become “cold” or “immune-resistant”, with resultant tumor growth and disease progression. Multiple factors are at play both at the cellular and host levels. The tumor microenvironment (TME) contributes the most to immune-resistance, with nutrient deficiency, hypoxia, acidity and different secreted inflammatory markers, all contributing to modulation of immune-metabolism and reprogramming of immune cells towards pro- or anti-inflammatory phenotypes. Both the tumor and surrounding immune cells require high amounts of glucose, amino acids and fatty acids to fulfill their energy demands. Thus, both compete over one pool of nutrients that falls short on needs, obliging cells to resort to alternative adaptive metabolic mechanisms that take part in shaping their inflammatory phenotypes. Aerobic or anaerobic glycolysis, oxidative phosphorylation, tryptophan catabolism, glutaminolysis, fatty acid synthesis or fatty acid oxidation, etc. are all mechanisms that contribute to immune modulation. Different pathways are triggered leading to genetic and epigenetic modulation with consequent reprogramming of immune cells such as T-cells (effector, memory or regulatory), tumor-associated macrophages (TAMs) (M1 or M2), natural killers (NK) cells (active or senescent), and dendritic cells (DC) (effector or tolerogenic), etc. Even host factors such as inflammatory conditions, obesity, caloric deficit, gender, infections, microbiota and smoking status, may be as well contributory to immune modulation, anti-tumor immunity and response to immune checkpoint inhibition. Given the complex and delicate metabolic networks within the tumor microenvironment controlling immune response, targeting key metabolic modulators may represent a valid therapeutic option to be combined with checkpoint inhibitors in an attempt to regain immune function.

scholarly journals Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1411 ◽  
Author(s):  
Irina Larionova ◽  
Elena Kazakova ◽  
Marina Patysheva ◽  
Julia Kzhyshkowska
Keyword(s):  
Fatty Acid ◽  
Immune Cells ◽  
Tumor Response ◽  
Macrophage Polarization ◽  
Innate Immune ◽  
Acid Oxidation ◽  
Innate Immune Cells ◽  
Primary Tumor Growth ◽  
Tumor Microenvironments ◽  
Functional Polarization

Macrophages are key innate immune cells in the tumor microenvironment (TME) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. The present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. We summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro- and anti-tumor activities. We also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex TME. We have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.

scholarly journals Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 137
Author(s):  
Zhi-Jian Han ◽  
Yang-Bing Li ◽  
Lu-Xi Yang ◽  
Hui-Juan Cheng ◽  
Xin Liu ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Immune Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Lymphatic Vessels ◽  
Cell Types ◽  
Mesenchymal Transition ◽  
Development Of Resistance ◽  
Immunosuppressive Cells

In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

P139 EFFECT OF LYSOSOMAL SHORT CHAIN FATTY ACID DELIVERY ON IMMUNE RESPONSE

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S12-S12
Author(s):  
Simon Strass ◽  
Constanze Heinzel ◽  
Natascha Cloos ◽  
Manuel Keppler ◽  
Jan Guse ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Immune Cells ◽  
Immune Modulation ◽  
Cytokine Production ◽  
Short Chain ◽  
Control Group ◽  
U937 Cells ◽  
Effective Response ◽  
Error Bars ◽  
Stimulation Of

Abstract Short chain fatty acids (SCFAs) are known as metabolites produced from gut microbiome fermenting dietary fibers and resistant starch. They are regulators of the interplay between the microbiome and its host and may have a role in the pathogenesis of inflammatory bowel disease (IBD). Free SCFAs influence intestinal epithelial and immune cells (e.g. macrophages and primary monocytes) through activation of free fatty acid receptors FFAR2 and FFAR3, inhibition of histone deacetylases (HDAC) and as a source of energy. SCFAs are known to impact cytokine production and differentiation of immune cells (e.g. Tumor necrosis factor alpha (TNFa), Interleukin (IL)-10, IL-6, IL-18, IL-1ß). We investigated the role of SCFAs in dextran sulfate sodium-induced colitis and their effect on the cytokine production by primary human immune cells. Treatment with SCFAs (acetate, propionate or butyrate) stimulated release of IL-1ß and IL-18 by buffy coat leukocytes or U937 cells without causing increased expression of corresponding genes. This raises the possibility of activation via the NLRP3 (NOD-, LRR- and pyrin domain- containing protein 3) inflammasome. NLRP3 is a multimeric inflammasome complex. Once activated, NLRP3 inflammasome releases caspase 1 leading to formation of mature IL-1ß and IL-18. Recent studies have shown that IL-1ß promotes phagocytosis and clearance of bacteria and aids the gut in eliciting an effective response in early stages of IBD. We asked whether this effect is mediated via surface or lysosomal (phagosomal) receptors? To answer this question, we prepared a series (SYD010) of novel compounds which are able to accumulate in the phagolysosome of immune cells through their macrolide backbone and deliver SCFAs, bound as esters to the lumen of the activated lysosome. In vitro, together with LPS stimulation, the substances modulated secretion of TNFa, IL-1ß, IL-10 and IL-6 at concentrations about 100x lower than free SCFAs (Figure 1). When tested in a DSS colitis mouse model, the SYD010 series caused a decrease in diarrhea scoring compared to the vehicle-treated control group at a concentration of 0.1 mg/kg (Figure 2) which corresponds to a total dose of ca. 100 nmol/kg (the compounds are systemically distributed). This is lower than the known luminal concentrations of SCFAs which is in the range of 40 mM. Our underlying hypothesis is that lysosomal reception of SCFAs leads to beneficial immune modulation in colitis in so far as stimulation of IL-1ß release promotes bacterial clearance. Furthermore, that concentrative uptake to the phagolysosome leads to enhanced stimulation of these receptors leading to responses at lower ambient concentrations or doses. We are assessing this substance class as potential IBD therapeutics. Figure 1. Effect of sodium butyrate or CSY4286 (lysosomal butyrate donor) on cytokine production by U937 cells. Supernatants were harvested after 24 h (IL-6) and 48 h (IL-1ß, IL-6) incubation with the test substances and cytokines determined by ELISA. The dotted line represents levels with LPS stimulation alone. SEM was applied for error bars. Figure 2. Results from DSS-induced (2.5% in drinking water) IBD study in BALB/c mice (8 mice per group). Scoring of body weight and diarrhea score over 8 days (a and b show data from final day of study). SEM was applied for error bars.

NT5E expression and the immune landscape of prostate cancer (PC): An analysis from The Cancer Genome Atlas database.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16591-e16591
Author(s):  
Abhishek Tripathi ◽  
Edwin Lin ◽  
Roberto Nussenzveig ◽  
Mark Yandell ◽  
Sumanta K. Pal ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
The Cancer Genome Atlas ◽  
Effector Memory ◽  
Marker Genes ◽  
Promote Tumor Growth ◽  
Tumor Phenotype ◽  
Tcga Dataset ◽  
Tumor Expression

e16591 Background: Immune checkpoint inhibitors targeting PD-1/L1 and CTLA-4 pathway have shown modest activity in patients with advanced PC. Additional immunosuppressive mechanisms in the PC tumor microenvironment need to be investigated. Increased CD73 (encoded by NT5E) expression results in generation of immunosuppressive adenosine in the tumor microenvironment and has been associated with metastasis and poor survival in PC. Utilizing the TCGA dataset, we investigated the association of NT5E expression with the immune landscape of PC. Methods: RNA-seq data for 331 PC tumor samples and 51 normal adjacent tissue (NAT) samples was downloaded and log2 transformed. Patients were split into low, intermediate, and high expression groups based on NT5E expression (≤ -1, -1 to 1 and ≥1 standard deviation from the overall mean) in tumor and NAT. A tumor inflammation signature (TIS) reflecting an inflamed tumor phenotype was calculated based on the averaged tumor expression of 18 previously validated genes (Ayers et al, 2017). Abundance of infiltrating immune cell subsets was estimated based on expression of previously identified 782 immune metagenes (Charoentong et al, 2017). Immune cell abundance scores and TIS were compared between NT5E expression groups using the Mann-Whitney U test and the Bonferroni correction was used to control for false discovery rate. Results: NT5E expression in NAT was not associated with the TIS or expression of immune cell marker genes. In contrast, NT5E expression in tumor tissue correlated positively with TIS (P < 0.001). Compared to tumors with low NT5E expression, those in high NT5E expression group had higher expression of central memory CD4+, effector memory CD8+, type 1 helper, NK and regulatory T (Treg) cell markers. Conclusions: In our analysis, NT5E expression correlated with markers of inflamed tumor phenotype in PC. Although NT5E expression was associated with higher CD8+and CD4+ T cells, concurrent increase in Tregs could inhibit the infiltrating lymphocytes and promote tumor growth. Our findings indicate a possible role for the adenosine pathway as a mediator of immunosuppression in PC and a potential therapeutic target. AT and EL: Equal contribution

scholarly journals Obesity-Related Fatty Acid and Cholesterol Metabolism in Cancer-Associated Host Cells

2020 ◽  
Vol 8 ◽  
Author(s):  
Ying Ye ◽  
Xiaoting Sun ◽  
Yongtian Lu
Keyword(s):  
Endothelial Cells ◽  
Fatty Acid ◽  
Tumor Microenvironment ◽  
Metabolic Regulation ◽  
Cholesterol Metabolism ◽  
Tumor Development ◽  
Host Cells ◽  
Acid Oxidation ◽  
Cancer Associated Fibroblasts ◽  
Future Perspectives

Obesity-derived disturbances in fatty acid and cholesterol metabolism are linked to numerous diseases, including various types of malignancy. In tumor cells, metabolic alterations have been long recognized and intensively studied. However, metabolic changes in host cells in the tumor microenvironment and their contribution to tumor development have been largely overlooked. During the last decade, research advances show that fatty acid oxidation, cholesterol metabolism, and lipid accumulation play critical roles in cancer-associated host cells such as endothelial cells, lymph endothelial cells, cancer-associated fibroblasts, tumor-associated myeloid cells, and tumor-associated lymphocytes. In addition to anti-angiogenic therapies and immunotherapy that have been practiced in the clinic, metabolic regulation is considered another promising cancer therapy targeting non-tumor host cells. Understanding the obesity-associated metabolism changes in cancer-associated host cells may ultimately be translated into therapeutic options that benefit cancer patients. In this mini-review, we briefly summarize the lipid metabolism associated with obesity and its role in host cells in the tumor microenvironment. We also discuss the current understanding of the molecular pathways involved and future perspectives to benefit from this metabolic complexity.

scholarly journals The Future of Cancer Diagnosis, Treatment and Surveillance: A Systemic Review on Immunotherapy and Immuno-PET Radiotracers

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2201
Author(s):  
Virginia Liberini ◽  
Riccardo Laudicella ◽  
Martina Capozza ◽  
Martin W. Huellner ◽  
Irene A. Burger ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Immune Cells ◽  
Fdg Pet ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Systemic Review ◽  
Imaging Biomarkers ◽  
Pet Radiotracers ◽  
18F Fdg

Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic landscape in oncology and improved patient prognosis in a variety of neoplastic diseases. However, to date, the selection of the best patients eligible for these therapies, as well as the response assessment is still challenging. Patients are mainly stratified using an immunohistochemical analysis of the expression of antigens on biopsy specimens, such as PD-L1 and PD-1, on tumor cells, on peritumoral immune cells and/or in the tumor microenvironment (TME). Recently, the use and development of imaging biomarkers able to assess in-vivo cancer-related processes are becoming more important. Today, positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is used routinely to evaluate tumor metabolism, and also to predict and monitor response to immunotherapy. Although highly sensitive, FDG-PET in general is rather unspecific. Novel radiopharmaceuticals (immuno-PET radiotracers), able to identify specific immune system targets, are under investigation in pre-clinical and clinical settings to better highlight all the mechanisms involved in immunotherapy. In this review, we will provide an overview of the main new immuno-PET radiotracers in development. We will also review the main players (immune cells, tumor cells and molecular targets) involved in immunotherapy. Furthermore, we report current applications and the evidence of using [18F]FDG PET in immunotherapy, including the use of artificial intelligence (AI).

scholarly journals Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Michaël Cerezo ◽  
Stéphane Rocchi
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Metabolic Pathways ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Limited Resources ◽  
Antitumor Response ◽  
Secondary Resistance

Abstract By targeting the tumor microenvironment to stimulate antitumor immunity, immunotherapies have revolutionized cancer treatment. However, many patients do not respond initially or develop secondary resistance. Based on the limited resources in the tumor microenvironment and competition between tumor and immune cells, the field of immune metabolism has produced extensive knowledge showing that targeting metabolism could help to modulate antitumor immunity. However, among all the different potentially targetable metabolic pathways, it remains unclear which have more potential to overcome resistance to immune checkpoint inhibitors. Here, we explore metabolic reprogramming in cancer cells, which might inhibit antitumor immunity, and strategies that can be used to favor the antitumor response.

scholarly journals Crosstalk Between the Tumor Microenvironment and Cancer Cells: A Promising Predictive Biomarker for Immune Checkpoint Inhibitors

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaoying Li ◽  
Yueyao Yang ◽  
Qian Huang ◽  
Yu Deng ◽  
Fukun Guo ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Small Proportion ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Cell Populations ◽  
Functional Interaction

Immune checkpoint inhibitors (ICIs) have changed the landscape of cancer treatment and are emerging as promising curative treatments in different type of cancers. However, only a small proportion of patients have benefited from ICIs and there is an urgent need to find robust biomarkers for individualized immunotherapy and to explore the causes of immunotherapy resistance. In this article, we review the roles of immune cells in the tumor microenvironment (TME) and discuss the effects of ICIs on these cell populations. We discuss the potential of the functional interaction between the TME and cancer cells as a predictive biomarker for ICIs. Furthermore, we outline the potential personalized strategies to improve the effectiveness of ICIs with precision.

scholarly journals Tumor Microenvironment Analysis Identified Subtypes Associated With the Prognosis and the Tumor Response to Immunotherapy in Bladder Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Hongxian Zhang ◽  
Jiwen Song ◽  
Junqiang Dong ◽  
Zhuo Liu ◽  
Lixuan Lin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Tumor Response ◽  
Checkpoint Inhibitors ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Genetic Characteristics ◽  
Signature Genes ◽  
Micro Rnas

Background: The efficiency of immune checkpoint inhibitors (ICIs) in bladder cancer (BLCA) treatment has been widely validated; however, the tumor response to ICIs was generally low. It is critical and urgent to find biomarkers that can predict tumor response to ICIs. The tumor microenvironment (TME), which may play important roles to either dampen or enhance immune responses, has been widely concerned.Methods: The cancer genome atlas BLCA (TCGA-BLCA) cohort (n = 400) was used in this study. Based on the proportions of 22 types of immune cells calculated by CIBERSORT, TME was classified by K-means Clustering and differentially expressed genes (DEGs) were determined. Based on DEGs, patients were classified into three groups, and cluster signature genes were identified after reducing redundant genes. Then TMEscore was calculated based on cluster signature genes, and the samples were classified to two subtypes. We performed somatic mutation and copy number variation analysis to identify the genetic characteristics of the two subtypes. Correlation analysis was performed to explore the correlation between TMEscore and the tumor response to ICIs as well as the prognosis of BLCA.Results: According to the proportions of immune cells, two TME clusters were determined, and 1,144 DEGs and 138 cluster signature genes were identified. Based on cluster signature genes, samples were classified into TMEscore-high (n = 199) and TMEscore-low (n = 201) subtypes. Survival analysis showed patients with TMEscore-high phenotype had better prognosis. Among the 45 differentially expressed micro-RNAs (miRNAs) and 1,033 differentially expressed messenger RNAs (mRNAs) between the two subtypes, 16 miRNAs and 287 mRNAs had statistically significant impact on the prognosis of BLCA. Furthermore, there were 94 genes with significant differences between the two subtypes, and they were enriched in RTK-RAS, NOTCH, WNT, Hippo, and PI3K pathways. The Tumor Immune Dysfunction and Exclusion (TIDE) score of TMEscore-high BLCA was statistically lower than that of TMEscore-low BLCA. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of TMEscore and tumor mutation burden (TMB) is 0.6918 and 0.5374, respectively.Conclusion: We developed a method to classify BLCA patients to two TME subtypes, TMEscore-high and TMEscore-low, and we found TMEscore-high subtype of BLCA had a good prognosis and a good response to ICIs.

scholarly journals Molecular Imaging in Immunotherapy: A Systematic Review

2021 ◽  
Author(s):  
Virginia Liberini ◽  
Riccardo Laudicella ◽  
Martina Capozza ◽  
Martin W. Hüllner ◽  
Irene A. Burger ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Immune Cells ◽  
Fdg Pet ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Immunohistochemical Analysis ◽  
Imaging Biomarkers ◽  
Pet Radiotracers ◽  
18F Fdg

Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic landscape in oncology and improved patient prognosis in a variety of neoplastic diseases. However, to date, the selection of the best patients eligible for these therapies, as well as the response assessment is still challenging. Patients are mainly stratified using immunohistochemical analysis of the expression of anti-gens on biopsy specimens, such as PD-L1 and PD-1, on tumor cells, on peritumoral immune cells, and/or in the tumor microenvironment (TME). Recently, the use and development of imaging biomarkers able to assess in-vivo cancer-related processes are becoming more important. Today, positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is used routinely to evaluate tumor metabolism, and also to predict and monitor response to immunotherapy. Although highly sensitive, FDG-PET, in general, is rather unspecific. Novel radiopharmaceuticals (immuno-PET radiotracers) able to identify specific immune system targets are under investigation in pre-clinical and clinical settings. In this review, we will provide an overview of the main new immuno-PET radiotracers in development. We will also review the main players (immune cells, tumor cells, and molecular targets) involved in immunotherapy. Furthermore, we report current applications and the evidence of using [18F]FDG PET in immunotherapy, including the use of artificial intelligence (AI).

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