A decrease in oxygen availability (hypoxia) can be encountered in solid tumors and has been associated with a poor outcome. Hypoxia can affect the function of many cells involved in tumor formation either directly or through the accumulation of adenosine. Both hypoxia and adenosine have been shown to inhibit the function of tumor infiltrating lymphocytes thus contributing to the failure of the immune system to fight cancer cells. The functionality of T lymphocytes relies on ion channels that control calcium (Ca2+) influx which is essential for the activation and function of these immune cells. Specifically two potassium channels, Kv1.3 and KCa3.1, play critical roles in the development and persistence of the Ca2+ response by regulating the driving force for Ca2+ influx. We have shown that hypoxia selectively inhibits the function and expression of Kv1.3 channels and decreases T cell proliferation and cytokine release. The mechanisms that mediate downregulation of Kv1.3 expression during hypoxia are not fully understood. Moreover, no information is available whether adenosine has any effect on these important channels and through them regulates T cell function. We have obtained preliminary evidence that adenosine inhibits the activity of KCa3.1 channels. Therefore, in the current application we will test the hypothesis that the microenvironment of solid tumors, and specifically hypoxia and adenosine, inhibit Kv1.3 and KCa3.1 channels producing a multidirectional attack on T cells that weakens the immune defense. We will perform experiments to identify the mechanisms that mediate downregulation of Kv1.3 expression in hypoxia. Furthermore, we will study the signaling pathways and functional relevance of KCa3.1 inhibition during hypoxia. We will also engineer multivalent nanoparticles to selectively target the expression of molecules involved in the decrease immune function by adenosine. Findings from the proposed studies will provide new insights into the mechanisms involved in decrease immune surveillance in solid tumors. Furthermore they will provide novel therapeutic targets and approaches to maintain the ability of immune cells to fight cancer cells in the hypoxic microenvironment.

Public Health Relevance

One of the functions of the immune system is to attack cancer cells and destroy them. Unfortunately, there are special conditions in tumors that inhibit immune cell ability to do this. We propose to study how the effects of those conditions on ion channels in the membrane of immune cells contribute to the failure of the immune system to destroy cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095286-09
Application #
8245787
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Mccarthy, Susan A
Project Start
2002-04-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$310,263
Indirect Cost
$108,130
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Chimote, Ameet A; Hajdu, Peter; Kottyan, Leah C et al. (2016) Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype. J Autoimmun 69:86-93
Hajdu, Peter; Martin, Geoffrey V; Chimote, Ameet A et al. (2015) The C-terminus SH3-binding domain of Kv1.3 is required for the actin-mediated immobilization of the channel via cortactin. Mol Biol Cell 26:1640-51
Hajdu, Péter; Chimote, Ameet A; Thompson, Tyler H et al. (2013) Functionalized liposomes loaded with siRNAs targeting ion channels in effector memory T cells as a potential therapy for autoimmunity. Biomaterials 34:10249-57
Chimote, Ameet A; Hajdu, Peter; Kucher, Vladimir et al. (2013) Selective inhibition of KCa3.1 channels mediates adenosine regulation of the motility of human T cells. J Immunol 191:6273-80
Kuras, Zerrin; Kucher, Vladimir; Gordon, Scott M et al. (2012) Modulation of Kv1.3 channels by protein kinase A I in T lymphocytes is mediated by the disc large 1-tyrosine kinase Lck complex. Am J Physiol Cell Physiol 302:C1504-12
Martin, Geoffrey V; Yun, Yeoheung; Conforti, Laura (2012) Modulation of T cell activation by localized Kýýý accumulation at the immunological synapse--a mathematical model. J Theor Biol 300:173-82
Chimote, Ameet A; Kuras, Zerrin; Conforti, Laura (2012) Disruption of kv1.3 channel forward vesicular trafficking by hypoxia in human T lymphocytes. J Biol Chem 287:2055-67
Kuras, Zerrin; Yun, Yeo-Heung; Chimote, Ameet A et al. (2012) KCa3.1 and TRPM7 channels at the uropod regulate migration of activated human T cells. PLoS One 7:e43859
Nicolaou, Stella A; Neumeier, Lisa; Takimoto, Koichi et al. (2010) Differential calcium signaling and Kv1.3 trafficking to the immunological synapse in systemic lupus erythematosus. Cell Calcium 47:19-28
Nicolaou, Stella A; Neumeier, Lisa; Steckly, Ashleigh et al. (2009) Localization of Kv1.3 channels in the immunological synapse modulates the calcium response to antigen stimulation in T lymphocytes. J Immunol 183:6296-302

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