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