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Understanding How Chronic Stress Impacts Radiation Therapy and the Immunosuppressive Tumor Microenvironment /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Understanding How Chronic Stress Impacts Radiation Therapy and the Immunosuppressive Tumor Microenvironment // Cameron Riker MacDonald.
Author:	MacDonald, Cameron Riker,
Description:	1 electronic resource (213 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
Subject:	Immunology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31998985
ISBN:	9798280779396

Understanding How Chronic Stress Impacts Radiation Therapy and the Immunosuppressive Tumor Microenvironment /
MacDonald, Cameron Riker,

Understanding How Chronic Stress Impacts Radiation Therapy and the Immunosuppressive Tumor Microenvironment /Cameron Riker MacDonald. - 1 electronic resource (213 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

Although novel therapies and improved treatment protocols have improved outcomes for many types of cancer, resistance to therapy and progression of disease continues to be a problem for many patients. Previous work from our laboratory and others has identified high levels of β-adrenergic receptor (β-AR) signaling in humans and mice as a potential contributor to poor outcomes. The ligands that bind β-ARs to induce signaling are known as catecholamines, and this family of neuroendocrine mediators includes epinephrine (EPI) and norepinephrine (NE). These catecholamines can be found in appreciable levels in circulation, and they can also be released locally into the tumor microenvironment (TME). In addition, while their levels are increased systemically due to acute stressors through a process commonly known as "the fight of flight" response, chronic activation of these signaling pathways can occur due to many other stressors, including psychological stress, anxiety, and persistent cold stress can also lead to prolonged periods of elevated systemic β-AR signaling. While previous research efforts from our laboratory have focused on understanding how β-AR signaling decreases the efficacy of chemotherapy, impairs T cell function, and limits the efficacy of anti-PD-1 immunotherapy, the goal of this research was to identify how β-AR signaling impacts the efficacy of radiation therapy (RT) and how β-AR signaling in the TME might promote immunosuppression driven by myeloid derived suppressor cells (MDSCs).Radiation therapy utilizes a focused beam of high energy ionizing radiation to hopefully kill all of the tumor cells that are targeted. In addition to directly killing these tumor cells, RT can initiate a process known as immunogenic cell death (ICD). ICD is a process by which dying tumor cells release antigens and damage associated molecular patterns (DAMPs) into the TME. These DAMPs include calreticulin, high mobility group box 1 (HMGB1), and adenosine triphosphate (ATP) in addition to many others. If this occurs to a sufficient degree and the anti-tumor immune system is functioning properly, then these antigens and DAMPs are detected and processed by immune cells, and an adaptive immune response is initiated. However, if insufficient amounts of DAMPs are produced, anti-tumor adaptive immune cells may not be activated and recruited to the TME, and the efficacy of the RT treatment will be limited. Here, we have identified β-AR signaling as a significant factor that reduces the efficacy of RT by limiting the production of several key DAMPs by tumor cells after RT, ultimately impairing the anti-tumor immune response. More specifically, knock down of the β2-AR gene in CT26.CL25 tumor cells increases the efficacy of RT in vivo in immune competent mice, but not immunodeficient mice. In addition, β2-AR knock down also increases the release of HMGB1 after in vitro RT treatments, and decreases the expression of the ATP catabolizing proteins CD39 and CD73, which results in increased conversion of ATP into adenosine. HMGB1 and ATP and both potent DAMPs, and adenosine is an immunosuppressive molecule. As a result, these data suggest that β2-AR signaling on tumor cells limits the efficacy of RT by decreasing DAMP accumulation in the TME by reducing the release of HMGB1, and increasing the breakdown of ATP into adenosine.In addition to these RT studies, we also investigated the role of β2-AR signaling on myeloid cell biology in the TME, specifically focusing on MDSCs. Interestingly, we found that human cancer patients and tumor bearing mice had significantly higher expression of β2-AR on their MDSCs compared to health controls. Using several different experimental approaches to limit, block, or eliminate β2-AR signaling, we observed a decrease in accumulation of MDSCs and delayed tumor growth. Mechanistically, we discovered that β2-AR signaling phosphorylates the key transcription factor, STAT-3, in MDSCs and can have significant effects on MDSC function. Specifically, β2-AR signaling increases T cell suppression by increasing Agr-1, Fas, and PD-L1 expression. In addition, β2-AR signaling in MDSCs increases their accumulation by decreasing the expression of pro-apoptotic proteins such as Caspase-8 and decreasing apoptosis as measured by phosphatidylserine expression staining with Annexin V. Concurrently, β2-AR signaling increases CPT-1a expression, fatty acid oxidation, oxidative phosphorylation, and autophagy, culminating in a more metabolically resilient and immunosuppressive MDSC.Taken together, these data reveal that β2-AR signaling promotes a more immunosuppressive TME by increasing the accumulation and immunosuppressive function of MDSCs. In addition, β2-AR signaling directly on tumor cells limits the efficacy of RT treatments by decreasing the production of DAMPs and reducing the subsequent activation of anti-tumor immunity. Although the majority of these studies were carried out using murine models of cancer, we believe that the mechanism(s) described in this work should be further investigated in human disease as well. These studies would provide further rationale to advocate for including stress reducing strategies as the standard of care for patients, or β-AR antagonists into treatment regimens.

English

ISBN: 9798280779396Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Norepinephrine

Understanding How Chronic Stress Impacts Radiation Therapy and the Immunosuppressive Tumor Microenvironment /
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520 $a Although novel therapies and improved treatment protocols have improved outcomes for many types of cancer, resistance to therapy and progression of disease continues to be a problem for many patients. Previous work from our laboratory and others has identified high levels of β-adrenergic receptor (β-AR) signaling in humans and mice as a potential contributor to poor outcomes. The ligands that bind β-ARs to induce signaling are known as catecholamines, and this family of neuroendocrine mediators includes epinephrine (EPI) and norepinephrine (NE). These catecholamines can be found in appreciable levels in circulation, and they can also be released locally into the tumor microenvironment (TME). In addition, while their levels are increased systemically due to acute stressors through a process commonly known as "the fight of flight" response, chronic activation of these signaling pathways can occur due to many other stressors, including psychological stress, anxiety, and persistent cold stress can also lead to prolonged periods of elevated systemic β-AR signaling. While previous research efforts from our laboratory have focused on understanding how β-AR signaling decreases the efficacy of chemotherapy, impairs T cell function, and limits the efficacy of anti-PD-1 immunotherapy, the goal of this research was to identify how β-AR signaling impacts the efficacy of radiation therapy (RT) and how β-AR signaling in the TME might promote immunosuppression driven by myeloid derived suppressor cells (MDSCs).Radiation therapy utilizes a focused beam of high energy ionizing radiation to hopefully kill all of the tumor cells that are targeted. In addition to directly killing these tumor cells, RT can initiate a process known as immunogenic cell death (ICD). ICD is a process by which dying tumor cells release antigens and damage associated molecular patterns (DAMPs) into the TME. These DAMPs include calreticulin, high mobility group box 1 (HMGB1), and adenosine triphosphate (ATP) in addition to many others. If this occurs to a sufficient degree and the anti-tumor immune system is functioning properly, then these antigens and DAMPs are detected and processed by immune cells, and an adaptive immune response is initiated. However, if insufficient amounts of DAMPs are produced, anti-tumor adaptive immune cells may not be activated and recruited to the TME, and the efficacy of the RT treatment will be limited. Here, we have identified β-AR signaling as a significant factor that reduces the efficacy of RT by limiting the production of several key DAMPs by tumor cells after RT, ultimately impairing the anti-tumor immune response. More specifically, knock down of the β2-AR gene in CT26.CL25 tumor cells increases the efficacy of RT in vivo in immune competent mice, but not immunodeficient mice. In addition, β2-AR knock down also increases the release of HMGB1 after in vitro RT treatments, and decreases the expression of the ATP catabolizing proteins CD39 and CD73, which results in increased conversion of ATP into adenosine. HMGB1 and ATP and both potent DAMPs, and adenosine is an immunosuppressive molecule. As a result, these data suggest that β2-AR signaling on tumor cells limits the efficacy of RT by decreasing DAMP accumulation in the TME by reducing the release of HMGB1, and increasing the breakdown of ATP into adenosine.In addition to these RT studies, we also investigated the role of β2-AR signaling on myeloid cell biology in the TME, specifically focusing on MDSCs. Interestingly, we found that human cancer patients and tumor bearing mice had significantly higher expression of β2-AR on their MDSCs compared to health controls. Using several different experimental approaches to limit, block, or eliminate β2-AR signaling, we observed a decrease in accumulation of MDSCs and delayed tumor growth. Mechanistically, we discovered that β2-AR signaling phosphorylates the key transcription factor, STAT-3, in MDSCs and can have significant effects on MDSC function. Specifically, β2-AR signaling increases T cell suppression by increasing Agr-1, Fas, and PD-L1 expression. In addition, β2-AR signaling in MDSCs increases their accumulation by decreasing the expression of pro-apoptotic proteins such as Caspase-8 and decreasing apoptosis as measured by phosphatidylserine expression staining with Annexin V. Concurrently, β2-AR signaling increases CPT-1a expression, fatty acid oxidation, oxidative phosphorylation, and autophagy, culminating in a more metabolically resilient and immunosuppressive MDSC.Taken together, these data reveal that β2-AR signaling promotes a more immunosuppressive TME by increasing the accumulation and immunosuppressive function of MDSCs. In addition, β2-AR signaling directly on tumor cells limits the efficacy of RT treatments by decreasing the production of DAMPs and reducing the subsequent activation of anti-tumor immunity. Although the majority of these studies were carried out using murine models of cancer, we believe that the mechanism(s) described in this work should be further investigated in human disease as well. These studies would provide further rationale to advocate for including stress reducing strategies as the standard of care for patients, or β-AR antagonists into treatment regimens.
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