title: Comparative analysis of innate immune system function in metastatic breast, colorectal, and prostate cancer patients with circulating tumor cells.
abstract: In recent years, circulating tumor cells (CTCs) in metastatic cancer patients have been found to be a promising biomarker to predict overall survival and tumor progression in these patients. A relatively high number of CTCs has been correlated with disease progression and poorer prognosis. This study was designed to assess innate immune system function, known to be responsible for the immune defense against developing neoplasms, in metastatic cancer patients with CTCs. Our aim is to provide a link between indication of poorer prognosis, represented by the number of CTCs to the cytotoxic activity of natural killer cells, an important component of the innate immune system, and to represent a promising expanded approach to management of metastatic cancer patients with CTCs. Seventy-four patients, with metastatic breast, colorectal, or prostate cancer, were recruited for this study. Using a flow cytometric assay, we measured natural killer (NK) cell cytotoxicity against K562 target cells; and CTCs were enumerated using the CellSearch System. Toll-like receptors 2 and 4 expression was also determined by flow cytometry. We found that within each of our three metastatic cancer patient groups, NK cell cytotoxic activity was decreased in patients with a relatively high number of CTCs in peripheral blood compared to patients with a relatively low number of CTCs. In the breast and prostate cancer group, patients with CTCs greater than 5 had decreased NK cell cytotoxicity when compared to patients with less than 5 CTCs. In the colorectal cancer group, we found that 3 or more CTCs in the blood was the level at which NK cell cytotoxicity is diminished. Additionally, we found that the toll-like receptors 2 and 4 expression was decreased in intensity in all the metastatic cancer patients when compared to the healthy controls. Furthermore, within each cancer group, the expression of both toll-like receptors was decreased in the patients with relatively high number of CTCs, i.e. greater than 5 for the breast and prostate cancer group and greater than 3 for the colorectal cancer group, compared to the patients with relatively low number, i.e. less than 5 or 3, respectively. Treatment options to increase NK cell cytotoxic activity should be considered in patients with relatively high numbers of CTCs.
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA. Electronic address: marksantos0219@gmail.com.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Santos
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Venkat K R
authors.initials: VK
authors.lastname: Mannam
authors.affiliation: Division of Oncology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Craft
authors.affiliation: Division of Oncology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Louis V
authors.initials: LV
authors.lastname: Puneky
authors.affiliation: Division of Oncology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Natale T
authors.initials: NT
authors.lastname: Sheehan
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lewis
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Julius M
authors.initials: JM
authors.lastname: Cruse
mesh_terms: D001943:Breast Neoplasms / Q000276:immunology*; D002452:Cell Count; D015179:Colorectal Neoplasms / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008297:Male; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
keywords: Circulating tumor cells; Innate immunity; Metastatic cancer; Natural killer cells; Toll-like receptors