Abstract
The type III interferon family (IFN-III), including IFN-λ3 (IL-28B), has antiviral, anti-tumor, and immunomodulatory activities. Although IL-28B anti-tumor effect has been extensively explored, its underlying anti-tumor mechanism remains unclear. Here, we explored IL-28B effects on colon cancer. We found that IL-28B significantly inhibited colon cancer growth in a murine MC38 tumor cell engraftment model. Interestingly, IL-28B did not directly promote apoptosis or inhibit MC38 tumor cell proliferation in vitro . IL-28B treatment exerted indirect anti-tumor activity by downregulating M2 macrophages in the tumor microenvironment. Furthermore, IL-28B inhibited M2 macrophage polarization in vitro. It also halted M2 macrophage differentiation predominantly via inhibition of the STAT3 and JNK signaling pathways. Our findings revealed that IL-28B inhibited M2 macrophages in the tumor microenvironment to delay colon cancer progression. Our study provides new evidence of IL-28B anti-tumor and immunomodulatory activities.
Keywords: IL-28B, Colorectal cancer, M2 macrophages, Cancer immunotherapy.
Introduction
Colorectal cancer (CRC) accounts for approximately 10% of cancer cases and cancer-related deaths worldwide each year. It is estimated that by 2035, the global incidence of CRC will increase to 25 million1. Traditional cancer treatment methods include surgery, radiotherapy, and chemotherapy; however, close to 50% of colon cancer cases recur post-treatment, and tumor recurrence often results in drug resistance. Therefore, novel and effective therapeutic options are urgently required against colon cancer2. Currently, immunotherapy is an accepted method for treating tumors, alone or in combination with more classic treatment options, such as chemotherapy. Changes in the immune system play an important role in cancer treatment. As mentioned above, IL-28B exhibits anti-tumor and immunomodulatory activities. Here, we aimed to explore the effects of IL-28B on colon cancer and decipher its underlying mechanisms.
IL-28B is a member of the IFN-III family (also known as IFN-λ3)3, 4. The IFN-III receptor consists of IL-28Rα and IL-10Rβ, which form the IFN-III heterodimeric receptor. IL-10Rβ is part of the IL-10 family of heterodimeric receptors5. IFN-III receptors are mainly distributed in cells of epithelial origin6. They are also distributed in specific immune cells, such as neutrophils, dendritic cells (DCs), monocytes, and natural killer cells7, 8.
Increasing evidence suggests that IFN-III participates in immune regulation9-11 and has antiviral effects12-14. Additionally, various studies have reported the anti-tumor effects of IFN-III in tumor models15. Yan et al. found a therapeutic synergy between IL-28B and sorafenib that suppresses hepatocellular carcinoma proliferation16. Tezuka et al. confirmed that IL-28A promotes apoptosis in lung cancer cells and exerts anti-tumor effects in a murine tumor model17. However, studies have shown that IFN-λ promotes tumor growth and metastasis in certain tumors. These data indicate that IL-28B plays an important role in tumorigenesis and development and may be targeted to develop new cancer treatment strategies. However, the role and mechanism of IL-28B in tumors remain poorly understood. In this study, we investigated the role of IL-28 in mouse colon cancer MC38 tumor models. Our results suggest that IL-28B, an anti-tumor cytokine, may potentially be used for the treatment of various cancers, including colon cancer.
Methods