Can respiratory hyperoxia mitigate adenosine-driven suppression of antitumor immunity? (original) (raw)
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Frontiers in immunology, 2017
In this minireview, we aim to highlight key factors of the tumor microenvironment, including adenosine, lactate, acidosis, vascular endothelial growth factor, phosphatidylserine, high extracellular K levels, and tumor hypoxia with respect to antitumor immune functions. Most solid tumors have an immature chaotic microvasculature that results in tumor hypoxia. Hypoxia is a key determinant of tumor aggressiveness and therapy resistance and hypoxia-related gene products can thwart antitumor immune responses.
The Critical Role of Hypoxia in Tumor-Mediated Immunosuppression
Hypoxia and Human Diseases, 2017
Underestimated for a long time, the involvement of the microenvironment has been proven essential for a better understanding of the cancer development. In keeping with this, the tumor is not considered anymore as a mass of malignant cells, but rather as an organ composed of various malignant and nonmalignant cell populations interacting with each other to create the tumor microenvironment. The tumor immune contexture plays a critical role in shaping the tumor immune response, and it is now well supported that such an immune response is impacted by the hypoxic stress within the tumor microenvironment. Tumor hypoxia is closely linked to tumor progression, metastasis, treatment failure, and escape from immune surveillance. Thus, hypoxia seems to be a key factor involved in creating an immune-suppressive tumor by multiple overlapping mechanisms, including the impairment of the function of cytotoxic immune cells, increasing the immunosuppressive properties of immunosuppressive cells, and activating resistance mechanism in the tumor cells. In this chapter, we review some recent findings describing how hypoxic stress in the tumor microenvironment hijacks the antitumor immune response.
Molecular & Cellular Proteomics, 2010
Under hypoxia, tumor cells produce secretion that modulates their microenvironment to facilitate tumor angiogenesis and metastasis. Here, we observed that hypoxic or reoxygenated A431 carcinoma cells exhibited enhanced angiogenic and metastatic potential such as reduced cell-cell and cell-ECM adhesion, increased invasiveness and produced secretion with increased chorioallantoic membrane angiogenic activity. Consistent with these observations, quantitative proteomic revealed that under hypoxia, the tumor cells secreted proteins involved in angiogenesis, focal adhesion, ECM-receptor interaction and immune cell recruitment. Unexpectedly, the secreted proteins were predominantly cytoplasmic and membrane proteins. Ultracentrifugation at 100,000g precipitated 54 % of the secreted proteins and enriched for many exosome-associated proteins such as the tetraspanins and alix, and also proteins with the potential to facilitate angiogenesis and metastasis. Two tetraspanins, CD9 and CD81 coimmunoprecipitated. Together, these suggested that tumor cells secrete proteins and exosomes with the potential to modulate their microenvironment and facilitate angiogenesis and metastasis.
Contemporary oncology (Poznan, Poland), 2018
Hypoxia characterizes growing tumors and contributes significantly to their aggressiveness. Hypoxia-inducible factors (HIFs 1 and 2) are stabilized and act differentially as transcription factors on tumor growth and are responsible for important cancer hallmarks such as pathologic angiogenesis, cellular proliferation, apoptosis, differentiation and genetic instability as well as affecting tumor metabolism, tumor immune responses, invasion and metastasis. Taking into account the tumor tissue as a whole and considering the interplay of the various partners which react with hypoxia in the tumor site lead to reconsideration of the treatment strategies. Key limitations of treatment success result from the adaptation to the hypoxic milieu sustained by tumor anarchic angiogenesis. This raises immune tolerance by influencing the recruitment of immunosuppressive cells as bone marrow derived suppressor cells (MDSC) or by impairing the infiltration and killing of tumor cells by cytotoxic cells...
Tumor Hypoxia: Causative Factors, Compensatory Mechanisms, and Cellular Response
The Oncologist, 2004
Learning Objectives After completing this course, the reader will be able to: Explain the effect of hypoxia on resistance to treatment. Describe the causes of tumor hypoxia. Characterize cellular response to hypoxia. Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com Hypoxia is a characteristic feature of locally advanced solid tumors resulting from an imbalance between oxygen (O2) supply and consumption. Major causative factors of tumor hypoxia are abnormal structure and function of the microvessels supplying the tumor, increased diffusion distances between the nutritive blood vessels and the tumor cells, and reduced O2 transport capacity of the blood due to the presence of disease- or treatment-related anemia. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of radiotherapy, some O2-dependent cytotoxic agents, and photodynamic therapy. Tumor hypoxia can also negatively impact therapeutic outcome ...
Hypoxia promotes tumor cell survival in acidic conditions by preserving ATP levels
Journal of Cellular Physiology, 2013
Abbreviations: 2-Deoxyglucose (2-DG); Extracellular pH (pH e); Hypoxia-inducible factor 1 and 2 (HIF1, HIF2), Hypoxia (Hx); Intracellular pH (pH i); Normoxia (Nx) † This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as
Tumor Hypoxia: Definitions and Current Clinical, Biologic, and Molecular Aspects
JNCI Journal of the National Cancer Institute, 2001
Tissue hypoxia results from an inadequate supply of oxygen (O 2) that compromises biologic functions. Evidence from experimental and clinical studies increasingly points to a fundamental role for hypoxia in solid tumors. Hypoxia in tumors is primarily a pathophysiologic consequence of structurally and functionally disturbed microcirculation and the deterioration of diffusion conditions. Tumor hypoxia appears to be strongly associated with tumor propagation, malignant progression, and resistance to therapy, and it has thus become a central issue in tumor physiology and cancer treatment. Biochemists and clinicians (as well as physiologists) define hypoxia differently; biochemists define it as O 2limited electron transport, and physiologists and clinicians define it as a state of reduced O 2 availability or decreased O 2 partial pressure that restricts or even abolishes functions of organs, tissues, or cells. Because malignant tumors no longer execute functions necessary for homeostasis (such as the production of adequate amounts of adenosine triphosphate), the physiology-based definitions of the term "hypoxia" are not necessarily valid for malignant tumors. Instead, alternative definitions based on clinical, biologic, and molecular effects that are observed at O 2 partial pressures below a critical level have to be applied. [
Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment
Immunology, 2014
Hypoxia is one of the hallmarks of the tumour microenvironment. It is the result of insufficient blood supply to support proliferating tumour cells. In response to hypoxia, the cellular machinery uses mechanisms whereby the low level of oxygen is sensed and counterbalanced by changing the transcription of numerous genes. Hypoxia-inducible factors (HIF) play a critical role in the regulation of cellular responses to hypoxia. In recent years ample evidence has indicated that HIF play a prominent role in tumour immune responses. Up-regulation of HIF1a promotes immune suppressive activity of myeloid-derived suppressive cells (MDSC) and tumour-associated macrophages (TAM) and rapid differentiation of MDSC to TAM. HIF1a does not affect MDSC differentiation to dendritic cells (DC) but instead causes DC activation. HIF inhibit effector functions of tumour-infiltrating lymphocytes. HIF1a inhibits regulatory T (Treg) cell development by switching the balance towards T helper type 17 cells. However, as a major part of Treg cell differentiation does not take place in the tumour site, a functionally more important role of HIF1a is in the promotion of Treg cell recruitment to the tumour site in response to chemokines. As a result, the presence of Treg cells inside tumours is increased. Hence, HIF play a largely negative role in the regulation of immune responses inside tumours. It appears that therapeutic strategies targeting HIF in the immune system could be beneficial for anti-tumour immune responses.