Browsing by Subject "Natural Killer Cells"
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Item Expression and Function of Immune Receptors in Pediatric Acute Lymphoblastic Leukemia(2016-12-01) Powers, Sheila B.; Stephen O. Mathew; Porunelloor A. Mathew; W. Paul BowmanAcute lymphoblastic leukemia (ALL) is a cancer that mainly affects children around the age of five. Due to current treatments, 80-90% of children achieve long-term remission. However, because of the current treatments, which include chemotherapy and CNS-directed radiation, these children may experience late effects which impact growth and development. Even though survival rate is high, quality of life can be greatly reduced for some of the survivors. Natural Killer (NK) cells are cells of the innate immune system that are important in fighting cancer and virally-infected cells. They have been a subject of interest in ALL because ALL of the B cell lineage is particularly resistant to NK cell killing. NK cells get activated by their surface receptors and their ligands on target cells. In B cell ALL, the NK cells do not appear to get the proper activating signals and this has been determined to be one reason this cancer is able to thrive. Our lab has cloned three immune receptors, 2B4 (CD244), CS1 (CRACC, CD319) and LLT1 (CLEC2D), that are expressed on NK cells as well as other immune cells. These receptors have been shown to play an important role in NK cell activation. Two other receptors, NKp30 and NKp46, are well-known activating receptors that have also been implicated in ALL. In this project I compared the mRNA and surface protein receptor expression of immune receptors between healthy subjects and ALL subjects. Altered expression of immune receptors was observed in ALL subjects. In particular, a significant decrease in mRNA expression of 2B4, LLT1 and NKp30 was observed in ALL subjects at diagnosis compared to healthy subjects. mRNA expression of CS1 was increased significantly after chemotherapy treatment. In contrast, NKp46 mRNA expression was significantly increased in ALL subjects as compared to healthy subjects. Cell surface protein expression of CS1 was significantly upregulated on T cells and monocytes and LLT1 on NK cells of ALL subjects at diagnosis. Interestingly, NKp30 was overexpressed on B cells, T cells, monocytes and NKp46 was overexpressed on T cells and monocytes but not on NK cells of ALL subjects at diagnosis. I also detected a significant increase of soluble CS1and BAT-3 in ALL subjects at diagnosis between the ages of 1-11 yrs. Also, soluble CD48 was significantly increased in ALL subjects after chemotherapy treatments. Future mechanistic studies may shed more light in the immune dysfunction in ALL ultimately contributing to better treatment options for patients with pediatric ALL.Item Extracellular Proliferating Cell Nuclear Antigen as a Marker and Therapeutic Target for Cancer Stem Cells.(2014-05-01) Horton, Nathan C.; Porunelloor MathewCancer is the second leading cause of death in the United States, making it a major public health issue. Due to increased efficiency in detecting and treating cancer, primary tumors account for only 10% of cancer mortalities. Today, the majority of cancer related deaths are due to metastasis and relapse after therapy, which current cancer treatments fail to prevent. Recently, cancer stem cells (CSCs) have emerged as being responsible for metastasis and relapse. CSCs are cancerous cells with stem cell characteristics including self renewal and the ability to evade chemotherapy and elimination by the immune system. A part of the innate immune system, Natural Killer (NK) cells provide the first line of defense against cancerous cells. NK cells kill cancerous cells through release of cytotoxic granules, a process regulated by activating and inhibitory receptors at the NK cell surface recognizing specific surface molecules on a tumor. Of the NK cell receptors, signaling via NKp44 is pivotal in determining the fate of tumor cells because it possesses both activating and inhibitory functions and is only expressed on activated NK cells. In this study, expression of Proliferating Cell Nuclear Antigen (PCNA), an inhibitory ligand of NKp44, is identified on the surface of a Diffuse B Cell Lymphoma, Prostate, and Breast cancer cell lines in novel association with Human Leukocyte Antigen Class I molecules. By blocking interactions between NKp44 and the PCNA/HLA I complex, NK cell mediated cytotoxicity and IFN-γ secretion is enhanced. Finally, prostate and breast cancer cells expressing PCNA at the cell surface express several molecular signatures of cancer stem cells which increase the ability of these cells to survive the metastatic process.