Factors of innate immunity in patients with colon cancer with different levels of circulating tumor cells.
Authors: Zlatnik Elena Yu , Novikova Inna A. , Bondarenko Elena S. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Petrov Dmitriy S. , Kolesnikov Vladimir E. , Savchenko Dmitriy A. , Tolmakh Roman E. , Dashkov Andrey V. , Katelnitskaya Oksana V. , Ilchenko Sergei A. , Dzhenkova Elena A. , Kit Oleg I. , Snezhko Aleksandr V. , Kolesnikov Evgeniy N. , Maksimov Aleksey Yu. , Shaposhnikov Aleksandr V. 
Published: June 2022

e15501

Background: The purpose of this study was to demonstrate the importance of circulating tumor cells (CTCs) in the formation of immunosuppression in colon cancer. Methods: 200 patients with stage II-IV colon cancer underwent surgery as the first stage of treatment. Blood levels of CTCs were determined before surgery by flow cytometry using the CellSearch method (the sample was considered positive with CTCs > 3), as well as some indicators of innate immunity (NK cells, neutrophilic and monocytic phagocytosis). Results: Regardless of the stage, patients with CTCs had statistically significantly lower levels of NK lymphocytes (16.8±1.9 versus 22.3±1.8%, p≤0.05) compared with the absence of CTCs; on the contrary, levels of NKT cells in this group were higher than in the absence of CTCs (8.8±0.9 versus 5.0±1.0%, p≤0.05). The presence of CTCs was accompanied by higher levels of CD16dim56bright cells (13.1±3.2 versus 5.9±1.0% p≤0.05) with a lower content of CD16+56dim (82.5±3.6 versus 90.4±0.8%), and levels of perforin and granzyme were similar. The presence of CTCs was characterized by a higher percentage of phagocytic monocytes in the Phagotest test, as well as a higher percentage of monocytes and neutrophils capable of developing oxidative burst upon fMLF stimulation in the Phagoburst test (10.8±3.3 versus 3.2±1.5% and 5.1 ±0.8 vs. 2.0±1.1%, respectively; p≤0.05). A separate analysis of phagocytosis indicators by disease stages revealed that the presence of CTCs in patients was accompanied by stimulation of phagocytosis in local tumors and inhibition in advanced disease, however, in the latter case, the ability of granulocytes and monocytes to generate reactive oxygen species (ROS) was preserved and even increased. Conclusions: The presence of CTCs in patients with colon cancer is characterized by a redistribution of natural killer subpopulations with an increase in the blood levels of NKT cells, some of which have immunosuppressive activity, due to a decrease in NK cells, and an increase in CD16dim56bright and a decrease in CD16+56dim, apparently, indicates disturbance of their maturation. The established changes in the presence of CTCs indicate the inhibition of antitumor properties of the NK cell and phagocytic components of innate immunity in tumor cell circulation. The N-formylpeptide fMLF is known as a powerful neutrophil chemoattractant, stimulator of their migration and cytokine production, which plays a role in the development of inflammatory bowel diseases. The growth-promoting activity described for the similar antimicrobial protein LL-37 can be mediated through neutrophil migration and ROS production. Thus, the presence of CTCs has a negative impact on the parameters of NK cell and phagocytic components of innate cellular immunity in patients with colon cancer, which can serve as one of the strategies for survival and dissemination of the tumor.