title: Low-doses of sequential-kinetic-activated interferon-γ enhance the ex vivo cytotoxicity of peripheral blood natural killer cells from patients with early-stage colorectal cancer. A preliminary study.
abstract: Natural killer (NK) cells are innate immune-system lymphocytes capable of killing tumor cells. They secrete cytokines, including interferon (IFN)-γ, which participate in shaping the initial inflammatory and downstream adaptive immune responses. Its potent immunoregulatory action means that IFN-γ might be beneficial in cases of tumor rejection, but its severe side-effects limit clinical applications. This pilot study compared low-dose IFN-γ prepared by sequential-kinetic-activation (SKA), with standard-dose recombinant (r) IFN-γ, in terms of ex-vivo cytotoxic activity of peripheral blood (PB)-NK cells from colorectal carcinoma (CRC) patients. This was tested against the NK-sensitive K562 cell line and the less-sensitive human CRC Caco-2 and HT-29 cell lines. Twenty primitive non-metastatic CRC patients, five metastatic CRC patients, and thirteen healthy donors were enrolled. PB lymphocytes (PBL) were exposed to medium alone, SKA-IFN-γ (0.25fg/ml) or rIFN-γ (1ng/ml). NK-cell cytolytic activity was examined via short-term (51)Cr-release. Pretreatment of PBL from non-metastatic patients with SKA-IFN-γ caused a significant increase in NK-cell cytotoxicity, compared to those from normal donors, although less markedly than pretreatment with rIFN-γ against all three cell lines. In contrast, PBL from metastatic CRC patients displayed significantly decreased NK-cell activity and responsiveness to both rIFN-γ and SKA-IFN-γ treatments. These results demonstrate in principle the immunomodulatory capacity of low-dose SKA-IFN-γ, and might open the door to the possibility of generating a novel, safe, and feasible approach to enhancing NK-cell antitumor activity in early-stage CRC patients.
authors.affiliation: Department of Surgical Sciences, University of Turin Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Radice
authors.affiliation: Clinical Research Unit, GUNA S.p.a., Milan Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Miranda
authors.affiliation: Department of Medical Sciences, University of Turin Italy. Electronic address: graziella.bellone@unito.it.
authors.forename: Graziella
authors.initials: G
authors.lastname: Bellone
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology*; D007371:Interferon-gamma / Q000737:chemistry / Q000494:pharmacology*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D007155:Immunologic Factors; D011994:Recombinant Proteins; D007371:Interferon-gamma
keywords: Cancer immunotherapy; Colorectal cancer; Interferon-γ; Low-dose cytokines; Natural killer cells