Characterization of Markers on Pancreatic and Colon Cancer Stem Cells to Enhance Natural Killer Cell Effector Functions




Malaer, Joseph D.


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Due to advancements in technology and medicine, the average human lifespan in the United States has increased to 79 years since the start of the 20th century. This increase in lifespan is also coupled with an increased risk of developing cancer. While cancer detection and initial treatment has increased the survival of patients, it is not a cure and patients wonder how long they will remain in remission. It is estimated that over 90% of cancer related deaths are due to relapse and metastasis. There is currently a growing body of research that indicates cancer stem cells (CSC) are responsible for relapse and metastasis. CSC are a small subpopulation of cells that retain self-renewal and pluripotency. These cells are also described as being quiescent, which may contribute to their chemotherapy resistance. Additionally, CSC are thought to express ligands to aid in immune evasion mechanisms. Natural Killer (NK) cells are lymphocytes of the innate immune system which function to combat infection and cancer. NK cells, unlike T and B cells, do not require prior sensitization. NK cell function is regulated through activating and inhibitory receptors. Recently, Proliferating Cell Nuclear Antigen (PCNA) was identified as an inhibitory ligand for the natural cytotoxicity receptor NKp44. Lectin-like transcript 1 (LLT1) expression is known to facilitate escape of NK cell effector functions in prostate and breast cancer, and now colorectal cancer. In this study we analyzed the expression of molecules on pancreatic and colon cancer cells that could allow escape from NK cell-mediated immune surveillance. The data presented here demonstrates surface PCNA expressing cells as CSC through co-expression of CSC surface markers CD44 and CD133 as well as overexpression of CSC transcription factors NANOG, SOX-2, and Oct-4. Blocking PCNA or NKp44 alters interferon-ℽ secretion by NK cells when cocultured with pancreatic and colon cancer cells. It is further demonstrated that blocking LLT1 or the PCNA-NKp44 interaction led to an increase in specific lysis of tumor cells. This study suggests that cell surface PCNA could function as a biomarker and an immunotherapeutic target for NK cell mediated killing of pancreatic cancer and colon cancer cells.