Repeated cycles of 5-fluorouracil chemotherapy impaired anti-tumor functions of cytotoxic T cells in a CT26 tumor-bearing mouse model

Abstract

BackgroundRecently, the immunostimulatory roles of chemotherapeutics have been increasingly revealed, although bone marrow suppression is still a common toxicity of chemotherapy. While the numbers and ratios of different immune subpopulations are analyzed after chemotherapy, changes to immune status after each cycle of treatment are less studied and remain unclear.ResultsTo determine the tumor-specific immune status and functions after different cycles of chemotherapy, we treated CT26 tumor-bearing mice with one to four cycles of 5-fluorouracil (5-FU). Overall survival was not improved when more than one cycle of 5-FU was administered. Here we present data concerning the immune statuses after one and three cycles of chemotherapy. We analyzed the amount of spleen cells from mice treated with one and three cycles of 5-FU as well as assayed their proliferation and cytotoxicity against the CT26 tumor cell line. We found that the absolute numbers of CD8 T-cells and NK cells were not influenced significantly after either one or three cycles of chemotherapy. However, after three cycles of 5-FU, proliferated CD8 T-cells were decreased, and CT26-specific cytotoxicity and IFN-γ secretion of spleen cells were impaired in vitro. After one cycle of 5-FU, there was a greater percentage of tumor infiltrating CD8 T-cells. In addition, more proliferated CD8 T-cells, enhanced tumor-specific cytotoxicity as well as IFN-γ secretion of spleen cells against CT26 in vitro were observed. Given the increased expression of immunosuppressive factors, such as PD-L1 and TGF-β, we assessed the effect of early introduction of immunotherapy in combination with chemotherapy. We found that mice treated with cytokine induced killer cells and PD-L1 monoclonal antibodies after one cycle of 5-FU had a better anti-tumor performance than those treated with chemotherapy or immunotherapy alone.ConclusionsThese data suggest that a single cycle of 5-FU treatment promoted an anti-tumor immune response, whereas repeated chemotherapy cycles impaired anti-tumor immune functions. Though the amount of immune cells could recover after chemotherapy suspension, their anti-tumor functions were damaged by multiple rounds of chemotherapy. These findings also point towards early implementation of immunotherapy to improve the anti-tumor effect.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-016-0167-7) contains supplementary material, which is available to authorized users.

Agarwood Extract Mitigates Intestinal Injury in Fluorouracil-Induced Mice

“…Previous studies in animal models have demonstrated that colon injury is induced by 5-FU and investigated the pathogenetic mechanisms of this damage. [17][18][19][20][21] Therefore, in the present study, we verified that intestinal injury is induced by 5-FU in mice. First, we found that WTAAE protected against 5-FU-induced colon damage using biochemical parameters and histological assessments.…”

“…16) However, in the clinic, 50-80% of patients who receive 5-FU report considerable side effects, such as diarrhea symptoms and gastrointestinal discomfort. 17) Intestinal injury is a severe limiting factor in clinical applications of 5-FU. 18) Previous studies in animal models have demonstrated that intestinal injury is induced by 5-FU, and the pathogenetic mechanisms of the drug has been investigated in experimental models.…”

Hepatoprotective Effect of Carboxymethyl Pachyman in Fluorouracil-Treated CT26-Bearing Mice

“…5-FU, an effective and clinical commonly used chemotherapeutic agent, can significantly inhibit the proliferation of tumors, at the cost of reducing the body mass, inducing liver injury, and suppressing the immunological function [ 8 ]. Previous studies have demonstrated liver injury induced by 5-FU in animal models, and most recently, pathogenetic mechanisms of liver injury induced by 5-FU has been investigated in experimental models [ 23 , 24 ].…”

“…5-Fluorouracil, a pyrimidine analogue that interferes with thymidylate synthesis, is a basic chemotherapeutic agent for the treatment of colorectal cancer [ 5 , 6 ], however, the development of drug-resistant phenotypes and systemic toxicity, especially liver injury, have become severe limiting factors in 5-FU therapy [ 7 , 8 , 9 ], and thereby 5-FU alone is of limited benefits in enhancing the survival of patients with advanced colorectal cancer. Emerging evidence indicates that 5-FU-induced liver injury is associated with multiple mechanisms, including 5-FU-induced inflammation, oxidative stress, and hepatocyte apoptosis [ 10 , 11 ].…”

Apoptotic effect of enterodiol, the final metabolite of edible lignans, in colorectal cancer cells

“…Cisplatin inhibits the progression of cancer by inducing DNA damage, whereas the antitumor drug 5‐fluorouracil has toxic effects on cancer cells . Owing to low therapeutic effectiveness, largely attributed to negative side effects of these chemicals, many natural products found in plants have been explored for anticancer therapy …”