Immunity, Hypoxia, and Metabolism–the Ménage à Trois of Cancer: Implications for Immunotherapy

It is generally accepted that metabolism is able to shape the immune response. Only recently we are gaining awareness that the metabolic crosstalk between different tumor compartments strongly contributes to the harsh tumor microenvironment (TME) and ultimately impairs immune cell fitness and effector functions. The major aims of this review are to provide an overview on the immune system in cancer; to position oxygen shortage and metabolic competition as the ground of a restrictive TME and as important players in the anti-tumor immune response; to define how immunotherapies affect hypoxia/oxygen delivery and the metabolic landscape of the tumor; and vice versa, how oxygen and metabolites within the TME impinge on the success of immunotherapies. By analyzing preclinical and clinical endeavors, we will discuss how a metabolic characterization of the TME can identify novel targets and signatures that could be exploited in combination with standard immunotherapies and can help to predict the benefit of new and traditional immunotherapeutic drugs.

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Immune System Efficiency in Cancer and the Microbiota Influence

Pathobiology ◽

10.1159/000512326 ◽

2021 ◽

pp. 1-17

Author(s):

Ana Margarida Barbosa ◽

Alexandra Gomes-Gonçalves ◽

António G. Castro ◽

Egídio Torrado

Keyword(s):

Immune Response ◽

Immune System ◽

Immune Checkpoint Inhibitors ◽

Therapeutic Response ◽

Checkpoint Inhibitors ◽

Critical Role ◽

Antitumor Immune Response ◽

System Efficiency ◽

Novel Targets ◽

Cancer Immunosurveillance

The immune system plays a critical role in preventing cancer development and progression. However, the complex network of cells and soluble factor that form the tumor microenvironment (TME) can dictate the differentiation of tumor-infiltrating leukocytes and shift the antitumor immune response into promoting tumor growth. With the advent of cancer immunotherapy, there has been a reinvigorated interest in defining how the TME shapes the antitumor immune response. This interest brought to light the microbiome as a novel player in shaping cancer immunosurveillance. Indeed, accumulating evidence now suggests that the microbiome may confer susceptibility or resistance to certain cancers and may influence response to therapeutics, particularly immune checkpoint inhibitors. As we move forward into the age of precision medicine, it is vital that we define the factors that influence the interplay between the triad immune system-microbiota-cancer. This knowledge will contribute to improve the therapeutic response to current approaches and will unravel novel targets for immunotherapy.

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Abstract 293: Cardiac Arrest and Resuscitation Causes Immunodeficiency That Involves the Hypothalamic-Pituitary-Adrenal Axis

Circulation ◽

10.1161/circ.138.suppl_2.293 ◽

2018 ◽

Vol 138 (Suppl_2) ◽

Author(s):

Yuntian Shen ◽

Qiang Zhao ◽

Jiangbo Wu ◽

Zhuoran Wang ◽

Wei Yang

Keyword(s):

Immune Response ◽

Cardiac Arrest ◽

Immune System ◽

Hpa Axis ◽

Time Course ◽

Immune Cell ◽

Infectious Complications ◽

Hypothalamic Pituitary Adrenal ◽

Immune Organs ◽

High Incidence

Introduction: Cardiac arrest (CA) is associated with high mortality and morbidity, which is in part due to infectious complications developed in CA patients. Infection complications, particularly pneumonia, occur in approximately 60% of CA patients. Given this high incidence, we hypothesized that after CA, the immune system is impaired, which increases the susceptibility of CA patients to potential infections. Therefore, in this study, we systematically examined the immune response in the brain and peripheral immune organs after CA. Methods: Mice were subjected to CA and cardiopulmonary resuscitation (CA/CPR). Flow cytometry, ELISA, immunohistochemistry, and quantitative PCR were used to analyze the immune response in various post-CA organs. Results: First, we characterized the time course of the immune response in the spleen after CA/CPR. CA/CPR induced significant changes in all major immune cell populations. Notably, B cell frequencies decreased, while T cell frequencies increased, in various organs on day 3 post-CA. Further, the levels of pro-inflammatory cytokines, eg IL-6, were markedly increased in the blood and brain after CA. Critically, we found that the lymphocyte counts in the spleen and thymus were dramatically lower in CA mice than in sham mice. Interestingly, CA/CPR caused progressive atrophy of the spleen and thymus. Since it has been shown that CA/CPR alters activity of the hypothalamic-pituitary-adrenal (HPA) axis, we speculated that CA-induced atrophy of lymphoid organs is mediated by the HPA axis. Thus, we treated CA mice with RU486, a glucocorticoid receptor antagonist. Indeed, this treatment reversed CA-induced organ atrophy and mitigated immune cell depletion, both in the thymus and spleen. Conclusions: We provided for the first time evidence that CA/CPR rapidly induced a systemic inflammatory response followed by impairment of the immune system, which eventually led to a massive loss of immune cells in the peripheral immune organs. This CA-induced immunodeficiency appears to be mediated by dysregulation of the HPA axis. Our findings here may be of high clinical significance, considering the high incidence of infectious complications in CA patients and their detrimental effects on CA outcome.

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The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity

Frontiers in Immunology ◽

10.3389/fimmu.2021.682435 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhengguo Wu ◽

Shang Li ◽

Xiao Zhu

Keyword(s):

Immune Response ◽

Immune System ◽

Tumor Microenvironment ◽

Cancer Immunotherapy ◽

Tumor Immunity ◽

Checkpoint Inhibitors ◽

The Body ◽

Research Progress ◽

Effective Population ◽

Cell Components

Cancer immunotherapy is a kind of therapy that can control and eliminate tumors by restarting and maintaining the tumor-immune cycle and restoring the body’s normal anti-tumor immune response. Although immunotherapy has great potential, it is currently only applicable to patients with certain types of tumors, such as melanoma, lung cancer, and cancer with high mutation load and microsatellite instability, and even in these types of tumors, immunotherapy is not effective for all patients. In order to enhance the effectiveness of tumor immunotherapy, this article reviews the research progress of tumor microenvironment immunotherapy, and studies the mechanism of stimulating and mobilizing immune system to enhance anti-tumor immunity. In this review, we focused on immunotherapy against tumor microenvironment (TME) and discussed the important research progress. TME is the environment for the survival and development of tumor cells, which is composed of cell components and non-cell components; immunotherapy for TME by stimulating or mobilizing the immune system of the body, enhancing the anti-tumor immunity. The checkpoint inhibitors can effectively block the inhibitory immunoregulation, indirectly strengthen the anti-tumor immune response and improve the effect of immunotherapy. We also found the checkpoint inhibitors have brought great changes to the treatment model of advanced tumors, but the clinical treatment results show great individual differences. Based on the close attention to the future development trend of immunotherapy, this study summarized the latest progress of immunotherapy and pointed out a new direction. To study the mechanism of stimulating and mobilizing the immune system to enhance anti-tumor immunity can provide new opportunities for cancer treatment, expand the clinical application scope and effective population of cancer immunotherapy, and improve the survival rate of cancer patients.

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Influence of immunological nutrition on treatment of patients with oncological profile

Perioperaciina Medicina ◽

10.31636/prmd.v1i1.3 ◽

2018 ◽

Vol 1 (1) ◽

pp. 19-24

Author(s):

M. O. Katrichenko ◽

I. I. Lisnyi

Keyword(s):

Immune Response ◽

Immune System ◽

Clinical Studies ◽

Animal Studies ◽

Immune Cell ◽

Laboratory Data ◽

Vital Role ◽

Biologically Active ◽

Protective Effects ◽

Immunological Reactions

In the reviewed article, we consider epidemiological and laboratory data that confirm the protective effects of biologically active nutrients in our diet for various diseases. Along with various factors such as alcohol, smoking, nutrition plays a vital role in influencing the patient’s immune response by transforming cells or by preventing, or acceleration of malignancy. Many data suggest that immunoactive nutrients control inflammatory and precancerous reactions in immune cells. Immunoprophylaxis is usually associated with modulation of the immune response when inflamed, thereby improving clinical outcomes. Different nutrients, including glutamine, arginine, vitamins, minerals and long-chain fatty acids, are important components of immunological nutrition. Clinical studies associated with these substances show different results with minimal effect. However, some studies have shown that these nutrients may have immunomodulatory effects that can reduce the risk of developing cancer. Pre-clinical studies claim that most of these nutrients have a positive effect in the complex treatment of cancer patients. In this article, we will consider the effect of the above nutrients on the immune system in patients of oncologic profile. Recent evidences suggest that immunological nutrition plays an important role in the development of cancer and its progression. Data from animal studies have clearly shown that the use of immunomodulatory nutrients isolated from food, by launching a cascade of immunological reactions, can detect and eliminate the tumor. Although the technology has evolved to such an extent that we can study each individual cytokine or function of the immune cell, it is difficult to demonstrate the powerful role of the immune system in preventing or treating cancer due to the complexity of the tumor cell or heterogeneity in different patients' populations. However, the study sheds light on interactions in immune responses and cancer development, prevention and therapeutic strategies that involve modulation through biologically active agents.

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Identification of Genetic Determinants of Pancreatic Cancer Immune Phenotypes by Integrative Genome-scale Analysis

10.21203/rs.3.rs-212097/v1 ◽

2021 ◽

Author(s):

Yuhang Ling ◽

Jiaqi Xu ◽

Xuedong Wang ◽

Jie Song ◽

Qiuhui Qian ◽

...

Keyword(s):

Pancreatic Cancer ◽

Immune Response ◽

Dna Damage ◽

Immune System ◽

Immune Cell ◽

Dna Damage Repair ◽

Cell Interactions ◽

Tumor Microenvironments ◽

Damage Repair ◽

Immune Phenotypes

Abstract Background Pancreatic cancer (PC) is a malignant neoplasm of the digestive tract that is highly malignant and difficult to diagnose at an early stage with high postoperative mortality and low cure rates. Cancer immunotherapy is innovating the clinical treatment of several cancers, but has a limited role in PC. The incomplete understanding of immune response hinders the development of gene therapy. To fill this gap, it is very necessary to classify the immunogenic subtypes of PC to understand the relationship between tumor microenvironments and clinical pathological characteristics, DNA damage repair and tumor immune response.Methods We extracted copy number change, somatic mutation and expression data from tumor genome map (TCGA). Using RNA sequencing data, we defined three different immunophenotypes and elucidated how immune cell interactions in immune subtypes vary with the background of the immune system. Further correlation analysis between DNA damage repair (DDR) related genes expression and immune response was conducted to explore the effects of DDR expression on antitumor activity in the tumor microenvironments.Results We defined three different immunophenotypes and elucidated how immune cell interactions in immune subtypes vary with the background of the immune system. When the total number of mutations was standardized, no enrichment of new epitopes was detected in immunocompetent phenotypes. These observations suggest that mutations in Th-1 enriched IS3 tumors are essentially no more immunogenic than those in IS2 cancers. We also found that the expression patterns of key IFN mediators STAT1 and / or STAT3 were increased in tumors with DDR mutations (19 of ATM, ERCC1, Rb1, BRCA2, pole and TP53), which is a reflex activation of IFN pathway.Conclusions Three defined immune subtypes show different characteristics of immune cell infiltration, revealing different manifestations in anti-cancer immune function. That is to say, clinical biological events of differential tumors are associated to immune-phenotypes. The invasive phenotype was driven by somatic mutations across immune subtypes, and DDR defect may also influence the response of tumor immune subtypes. Our results suggested that the occurrence of pancreatic cancer is related to genetic factors of immunophenotype, providing information for clinical prognosis and outcome of pancreatic cancer.

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TrackSOM: mapping immune response dynamics through sequential clustering of time- and disease-course single-cell cytometry data

10.1101/2021.06.08.447468 ◽

2021 ◽

Author(s):

Givanna Haryono Putri ◽

Jonathan Chung ◽

Davis N Edwards ◽

Felix Marsh-Wakefield ◽

Suat Dervish ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

West Nile Virus ◽

Immune Cells ◽

Immune Cell ◽

West Nile Virus Infection ◽

Cell Populations ◽

Disease Course ◽

Response Dynamics ◽

Over Time

Mapping the dynamics of immune cell populations over time or disease-course is key to understanding immunopathogenesis and devising putative interventions. We present TrackSOM, an algorithm which delineates cellular populations and tracks their development over a time- or disease-course of cytometry datasets. We demonstrate TrackSOM-enabled elucidation of the immune response to West Nile Virus infection in mice, uncovering heterogeneous sub-populations of immune cells and relating their functional evolution to disease severity. TrackSOM is easy to use, encompasses few parameters, is quick to execute, and enables an integrative and dynamic overview of the immune system kinetics that underlie disease progression and/or resolution.

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Lifting the innate immune barriers to antitumor immunity

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000695 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000695 ◽

Cited By ~ 5

Author(s):

Carla V Rothlin ◽

Sourav Ghosh

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Immune System ◽

T Cell ◽

Time Course ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Cell Activity ◽

Innate Immune ◽

Cell Functions

The immune system evolved for adequate surveillance and killing of pathogens while minimizing host damage, such as due to chronic or exaggerated inflammation and autoimmunity. This is achieved by negative regulators and checkpoints that limit the magnitude and time course of the immune response. Tumor cells often escape immune surveillance and killing. Therefore, disrupting the brakes built into the immune system should effectively boost the anticancer immune response. The success of anti-CTLA4, anti-PD-1 and anti-PD-L1 have firmly established this proof of concept. Since the response rate of anti-CTLA4, anti-PD-1 and anti-PD-L1 is still limited, there is an intense effort for the identification of new targets and development of approaches that can expand the benefits of immunotherapy to a larger patient pool. Additional T cell checkpoints are obvious targets; however, here we focus on the unusual suspects—cells that function to initiate and guide T cell activity. Innate immunity is both an obligate prerequisite for the initiation of adaptive immune responses and a requirement for the recruitment of activated T cells to the site of action. We discuss some of the molecules present in innate immune cells, including natural killer cells, dendritic cells, macrophages, myeloid-derived suppressor cells, endothelial cells and stromal cells, that can activate or enhance innate immune cell functions, and more importantly, the inhibitors or checkpoints present in these cells that restrain their functions. Boosting innate immunity, either by enhancing activator functions or, preferably, by blocking the inhibitors, may represent a new anticancer treatment modality or at least function as adjuvants to T cell checkpoint inhibitors.

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Immune gene expression profiles in high-grade urothelial carcinoma of the bladder: a NanoString study

Journal of Clinical Pathology ◽

10.1136/jclinpath-2020-206631 ◽

2020 ◽

Vol 74 (1) ◽

pp. 53-57 ◽

Cited By ~ 2

Author(s):

Ekaterina Olkhov-Mitsel ◽

Anjelica Hodgson ◽

Stanley K Liu ◽

Danny Vesprini ◽

Jane Bayani ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Immune Evasion ◽

Messenger Rna ◽

Immune Cell ◽

Expression Profiles ◽

Differentially Expressed Gene ◽

Immune Gene ◽

High Grade ◽

Predictive Values

AimsThe advent of immune checkpoint inhibitor therapy has proven beneficial in a subset of high-grade urothelial carcinomas (HGUC) of the bladder. Although treatment selection is currently largely determined by programmed death-ligand 1 (PD-L1) status, multiple factors in the immune system may modulate the host immune response to HGUC and immunotherapy. In this pilot study, we used a transcriptomic approach to identify the immune milieu associated with PD-L1 expression to enhance our understanding of the HGUC immune evasion network.MethodsThe immune transcriptome of 40 HGUC cystectomy cases was profiled using the NanoString nCounter Human V.1.1 PanCancer Panel. All cases were assessed for associated PD-L1 status (SP263) using whole tissue sections. PD-L1 status was determined as high or low using 25% tumour and/or immune cell staining.ResultsThe most significantly differentially expressed gene was PD-L1 messenger RNA (CD274), which strongly correlated with protein expression (r=0.720, p<0.001). The sensitivity, specificity, positive and negative predictive values of CD274 for PD-L1 expression were 85%, 96%, 92% and 93%, respectively. The PD-L1 associated gene signature also included complement components C1QA and CD46 and NOD2 (innate immune system), proinflammatory cytokines CXCL14, CXCL16, CCL3, CCL3L1 and OSM along with the immune response mediator SMAD3, among others. Pathway analysis determined enrichment of these genes in interleukin-10 production, lymphocyte chemotaxis and aberrant IFNγ, NF-κB and ERK signalling networks.ConclusionsWe report key genes and pathways in the immune transcriptome and their association with PD-L1 status, which may be involved in immune evasion of HGUC and warrants further investigation.

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IL-12 Gene Electrotransfer Triggers a Change in Immune Response within Mouse Tumors

Cancers ◽

10.3390/cancers10120498 ◽

2018 ◽

Vol 10 (12) ◽

pp. 498 ◽

Cited By ~ 13

Author(s):

Guilan Shi ◽

Chelsea Edelblute ◽

Sezgi Arpag ◽

Cathryn Lundberg ◽

Richard Heller

Keyword(s):

Immune Response ◽

T Cells ◽

Tumor Microenvironment ◽

Mononuclear Cells ◽

Immune Cell ◽

Immune Memory ◽

Control Group ◽

Gene Electrotransfer ◽

Cell Content ◽

Peripheral Blood Mononuclear

Metastatic melanoma is an aggressive skin cancer with a relatively low survival rate. Immune-based therapies have shown promise in the treatment of melanoma, but overall complete response rates are still low. Previous studies have demonstrated the potential of plasmid IL-12 (pIL-12) delivered by gene electrotransfer (GET) to be an effective immunotherapy for melanoma. However, events occurring in the tumor microenvironment following delivery have not been delineated. Therefore, utilizing a B16F10 mouse melanoma model, we evaluated changes in the tumor microenvironment following delivery of pIL-12 using different GET parameters or injection of plasmid alone. The results revealed a unique immune cell composition after intratumoral injection of pIL-12 GET. The number of immune memory cells was markedly increased in pIL-12 GET melanoma groups compared to control group. This was validated using flow cytometry to analyze peripheral blood mononuclear cells as well as delineating immune cell content using immunohistochemistry. Significant differences in multiple cell types were observed, including CD8+ T cells, regulatory T cells and myeloid cells, which were induced to mount a CD8+PD1− T cells immune response. Taken together, these findings suggest a basic understanding of the sequence of immune activity following pIL-12 GET and also illuminates that adjuvant immunotherapy can have a positive influence on the host immune response to cancer.

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Interleukin-32 in Infection, Inflammation and Cancer Biology

Serbian Journal of Experimental and Clinical Research ◽

10.1515/sjecr-2016-0085 ◽

2020 ◽

Vol 21 (1) ◽

pp. 75-82

Author(s):

Mladen Pavlovic ◽

Ivan Jovanovic ◽

Nebojsa Arsenijevic

Keyword(s):

Immune Response ◽

Immune System ◽

Immune Cells ◽

Proinflammatory Cytokine ◽

Cancer Biology ◽

Clonal Expansion ◽

Acquired Immunity ◽

Effector Functions

AbstractCytokines are small pleiotropic polypeptids secreted dominantly by the cells of the immune system. These polypeptids are main mediators of innate and acquired immunity, responsible for clonal expansion and differentiation of immune cells, initiation of immune response and enhancing of effector functions of leukocytes. Cytokine-related effects are most studied in the fields of inflammation, immunology, and cancer biology. In this review we discuss one of the most intriguing, recently discovered proinflammatory cytokine, interleukin 32.

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