A cytokine signal inhibitor for rheumatoid arthritis enhances cancer metastasis via depletion of NK cells in an experimental lung metastasis mouse model of colon cancer

Abstract

Abstract. Current therapy for rheumatoid arthritis (RA) relies on global suppression of the immune response or specific blockade of inflammatory cytokines. However, it is unclear how immunosuppressants affect patients with cancer. Therefore, in the present study, the effect of three biological agents, tofacitinib, anti-mouse IL-6 receptor antibody (MR16-1) and etanercept, which are used for the treatment of RA diseases, on a tumor-bearing mouse model was investigated. The effect of the three agents was examined using a mouse lung-metastasis model with the murine colon 26 cancer cell line. Lymphocyte subsets and natural killer (NK) cells in peripheral blood and spleen were analyzed using fluorescence-activated cell sorting, and the number of lung surface nodules was examined. In the continuous tofacitinib administration (15 mg/kg/day) group, the number of lung surface nodules was significantly increased compared with that of the vehicle-treated group (vehicle, 1.20±0.58; tofacitinib, 35.6±10.81; P<0.01). NK cell number in the blood and spleen of tofacitinib-treated mice was decreased 10-fold, and the percentage of cluster of differentiation (CD)11 + CD27 -NK cells was significantly reduced. MR16-1 [8 mg/mouse; once a week; intraperitoneal (i.p.)] or etanercept (1 mg/mouse; 3 times a week; i.p.) treatment did not affect the number of NK cells or lung metastasis. In the present study, immunosuppressants that target cytokines, including tofacitinib, were demonstrated to inhibit the proliferation and differentiation of NK cells, and exhibit the potential to promote cancer metastasis using a mouse model of lung metastasis. IntroductionImmune cells are associated with carcinogenesis, tumor growth, invasion and metastasis. Natural killer (NK) cells in particular serve an important role in immune surveillance, and are generally accepted as a beneficial cell population for anti-tumor immunity (1). Several studies have reported that depletion of NK cells causes increased survival of circulating tumor cells, resulting in enhanced cancer metastasis (2-5). In addition, it has been suggested that a favorable prognosis is associated with the extent of NK cell infiltration into the tumor in patients with gastric cancer or colorectal cancer (6,7). Therefore, inhibition of NK cell activity may promote cancer metastasis through a decrease in the number of NK cells.In addition, cluster of differentiation (CD)4 + and CD8 + T cells, which are specific for tumor-associated antigens, serve important roles in antitumor immunity (8,9). CD4 + T cells serve an important role in generating effective immune responses by stimulating CD8 + T cell proliferation and establishing long-lived functional T cell memory (8). It has been reported that CD4 + T cell can enhance CD8 + T cell recruitment and infiltration into tumors (8). Similarly, several reports have suggested that the infiltration of CD8 + T cells is associated with a better prognosis in colon cancer (10).Several inflammatory cytokines, including tumor necrosis factor (TNF)-α and interl...

Resveratrol inhibits the invasion and metastasis of colon cancer through reversal of epithelial‑ mesenchymal transition via the AKT/GSK‑3β/Snail signaling pathway

“…SW480 cells transfected with si-AKT1 or NC were collected, and the density was adjusted to 3×10 7 cells/ml with normal saline. Each nude mouse was inoculated with 0.2 ml cell suspension into the tail vein to establish a lung metastasis model of colon cancer (25,26). Two weeks after inoculation, disease progression was assessed using live fluorescence imaging.…”

Therapeutic effects of tyroserleutide on lung metastasis of human hepatocellular carcinoma SK-HEP-1 and its mechanism affecting ICAM-1 and MMP-2 and -9

“…The specimen of tumor tissue was embedded in paraffin and routinely stained with H&E. Histopathology analysis was performed with a light microscope (Olympus, Tokyo, Japan), and the numbers of metastatic lung nodules were also calculated. 3 The rate of metastasis inhibition (%)=(1-the number of metastatic nodules of drug group/the number of metastatic nodules of the control)×100.…”

Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis

“…Tofacitinib inhibits signal transduction of several cytokines, including type I and type II interferons, and decreases the number of NK cells, both of which are relevant to the elimination of transformed cells in the process of cancer immunoediting [43]; thus, particular concerns about the risk of malignancy in patients treated with tofacitinib have been raised. In an experimental lung metastasis mouse model of colon cancer, continuous tofacitinib administration (15 mg/kg/day) significantly inhibited the proliferation and differentiation of NK cells and significantly increased the number of metastatic lung surface nodules [44]. Currently available evidence, however, does not indicate an increased risk of malignancy in RA patients treated with tofacitinib.…”