Antitumor immunity of low-dose cyclophosphamide: changes in T cells and cytokines TGF-beta and IL-10 in mice with colon-cancer liver metastasis

Abstract

Background The tumor immune microenvironment is one of the most important prognostic factors in liver metastasis from colorectal cancer. Low-dose cyclophosphamide (CTX) is widely believed to be involved in the modulation of the immune system. However, the underlying mechanism of low-dose CTX remains unknown. This study aimed to investigate the antitumor immunity of low-dose CTX in the treatment of colon-cancer liver metastasis. Methods Thirty mice were randomly divided into five groups. After liver metastasis was established in colon-cancer models, mice in the treatment groups were injected with low-dose CTX (20 mg/kg) at different time points. Liver and spleen tissues were examined for T-cell markers via flow cytometry. Interleukin (IL)-10 and transforming growth factor (TGF)-β1 expression levels in liver tissues were analysed by immunohistochemistry. Serum interferon (IFN)-γ and IL-10 levels were detected by enzyme-linked immunosorbent assay. An additional 20 mice were randomly allocated into two groups and the survival times were recorded. Results The expression levels of CD4+ T cells, CD8+ T cells, and IFN-γ were down-regulated, whereas those of IL-10 and TGF-β1 were up-regulated in liver metastasis from colon cancer in mice. Furthermore, the local and systemic microenvironments of the liver were altered, which led to reduced antitumor immune responses and subsequently liver metastasis. However, treatment with low-dose CTX reversed these effects. The survival times of mice treated with low-dose CTX were significantly longer than those of the other groups. Conclusions Low-dose CTX exerts its antitumor activity by changing the systemic and local immune microenvironments and enhancing immune regulation in mice. CTX could be used as a drug to prevent and treat liver metastasis from colon cancer.

A phase II randomised, placebo-controlled trial of low dose (metronomic) cyclophosphamide and nintedanib (BIBF1120) in advanced ovarian, fallopian tube or primary peritoneal cancer

“…Additionally, modulation of the abnormal tumour vasculature by OMC may enhance an immune-supportive tumour microenvironment eg. allowing accumulation of effector T cells, leading to prolonged responses/disease stabilisation in small groups of patients 28,29 . (Appendix Figure 3.)…”

Past, Present and Future of Oncolytic Reovirus

“…Thus, identifying appropriate dosing schedules is essential. For example, low-dose CPA effectively enhances reovirus delivery to tumours while maintaining protective NAb levels [114] and, crucially, has the potential to promote the development of anti-tumour immunity [143,144], although in the context of reovirus this remains unknown Given the initial belief that NAbs would be detrimental to efficacy, the concept of using cellular chaperones to deliver reovirus to tumours was explored. Immune cells have excellent tumour trafficking potential, and also have the potential to enhance anti-tumour immune effects.…”

Treatment with lentiviral vectors encoding shRNA against interleukin 10 modulates the immunosuppressive activity of murine colon carcinoma‑associated myeloid‑derived suppressor cells

“…It was proved that CY used in low doses causes the selective elimination of regulatory T lymphocytes, and by inducing immunogenic death of cancer cells, at the same time contributes to the increase in the activity of effector T lymphocytes and supports the formation of immune memory ( 32 ). As a result of the changes of the immune landscape mediated by CY, a decrease of IL-10 expression is often observed ( 33 – 35 ). In fact, production of IL-10 by cells isolated from tumors was decreased not only in CY and shIL-10 LV-treated groups, but a slight decrease was also observed in groups treated with CY as well as CY and shN LVs.…”