Interferons (IFNs) are critical in protecting the body from viruses and cancer, helping to recognize and destroy viral particles and cancer cells by activating immune responses. There are three types of interferons: I, II, and III:
- IFN-I (e.g., IFN-α and IFN-β) initiate the body’s antiviral defense and enhance the activity of genes that stimulate the immune response to infections.
- IFN-II (IFN-γ) is secreted by killer cells, T-helper 1 cells, and cytotoxic effector cells. IFN-II activates receptors on various cells, excluding erythrocytes.
- IFN-III (IFN-λ) affects epithelial and immune cells, functioning similarly to IFN-I.
Facts about Interferons:
- Interferons help limit viral replication by activating natural killer (NK) cells, which destroy infected cells.
- IFNs stimulate the maturation of antigen-presenting cells, support the survival of virus-specific CD4 and CD8 T cells, enhance B cell activation, and initiate cell death.
- Cells begin producing IFN-I when pattern recognition receptors (PRRs) detect pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs).
- The production of IFN-I is also influenced by cytokines such as CSF1, RANK, and estrogens.
- The target of rapamycin (mTOR), a nutrient detector, is required for altering lipid metabolic pathways and IFN-I production.
- IFN production is crucial for biosynthesis and cellular metabolism.
- Microbiota plays a significant role in maintaining stable and effective immune system functioning, supporting normal interferon levels in the body. These levels regulate innate immune responses and maintain homeostasis.
Cancer Cells:
Some interferon-stimulated genes (ISGs) help cancer cells resist DNA damage caused by chemotherapy or radiation, as type I interferons, produced in response to viruses, also protect cancer cells from damage. IFN-I promotes cancer cell resistance to treatment at low concentrations, but they become toxic to these cells at high concentrations.
In some tumor types, IFN-I can inhibit epithelial-mesenchymal transition (EMT)—a process where epithelial cells, usually stationary and connected, transform into mobile mesenchymal cells that can penetrate tissues. EMT increases cancer cells’ ability to move to other body parts and is crucial in cancer metastasis.
The cytokine oncostatin M can have effects opposite to interferon, promoting metastasis.
Type I interferons stimulate the maturation of dendritic cells and activate NK, T, and B cells to enhance the immune response against cancer. IFN-I helps T cells destroy tumor cells by reducing immunosuppression in the tumor microenvironment. IFN-I suppresses immunosuppressive cells that support tumor growth and stimulates pro-inflammatory macrophages that aid in killing cancer cells.
Proteins Schlafen (SLFN) and Enzyme ULK1 are vital in the anti-cancer immune response. The absence of ULK1 reduces the expression of IFN-γ-dependent genes involved in inflammation regulation. SLFN proteins participate in cell growth, differentiation, immune reactions, and antiviral activity. Some SLFN proteins are associated with pathological conditions:
- SLFN5 is linked to stomach cancer risk.
- SLFN14 alterations are related to severe thrombocytopenia and abnormal platelet production, leading to excessive bleeding.
- Elevated SLFN11 levels are associated with breast and lung cancer.
- SLFN5 can suppress the anti-cancer immune response.
SLFN proteins can stimulate IFN responses with anti-tumor and antiviral effects but can also delay these responses.
Dendritic Cells (DCs) and the cGAS-STING Pathway:
IFN-I stimulates the maturation and activity of DCs, which transport antigens to lymph nodes to activate T cells. DCs trigger an immune response against tumors by presenting tumor-associated antigens to CD8 T cells.
A critical immune system component is the cGAS-STING pathway, which activates immune responses to tumors. Tumor cells can release their DNA into the cytoplasm, where the cGAS receptor recognizes it. This receptor activates the cGAMP molecule, which binds to the STING protein in the cell. STING moves to the cell nucleus and initiates a cascade of reactions, activating proteins like TBK1 and IRF3. These proteins move to the nucleus, activating genes that produce IFN-I, essential for tumor immune response.
IFN-I stimulates the migration of effector T cells into tumors and enhances antigen presentation. However, in some cases, IFN-I can induce immunosuppressive effects in the tumor microenvironment, protecting the tumor from immune responses.
Natural Killer (NK) Cells
NK cells are immune system cells that fight tumors and viruses. They develop from lymphoid progenitors and become active under the influence of inflammatory cytokines such as IFN, IL-2, IL-12, and IL-15. These cytokines activate the JAK-STAT signaling pathway, promoting NK cells’ growth, development, and function.
JAK and STAT play critical roles in developing and functioning NK cells. JAK (Janus kinase) and STAT (Signal Transducer and Activator of Transcription) are proteins necessary for intracellular signal transmission. JAK are enzymes that activate when specific molecules bind to receptors on the cell surface. Once activated, JAK phosphorylates STAT proteins—adding phosphate groups to them. Phosphorylated STAT proteins move to the cell nucleus and initiate gene expression that regulates various cellular processes and immune responses. STAT1 is an essential regulator of NK cell maturation and cytotoxicity, controlling tumors.
JAK2 activity supports the development of dendritic cells. Dendritic cells produce IL-15, which is crucial for NK cell activation and enhancing their antitumor action. Using IL-15 in therapy can prevent tumor spread.
T-Cells
Type I interferons are critical in activating CD8 T-cells, promoting their growth, development, and ability to form memory cells. The JAK-STAT signaling pathway can influence the immune response of T-cells. In mice, the absence of the IFNAR1 receptor for type I interferons in cancer cells led to an enhanced anti-tumor response from CD8 T-cells following ionizing radiation. However, malignant cells were more sensitive to the cytotoxicity of CD8 T-cells.
IFN-I and IFN-γ can exert immunosuppressive effects on cancer cells through molecules such as PD-L1 and LGALS9. Persistent interferon signaling can alter the genetic activity of cancer cells, making them more resistant to immunotherapy. High levels of PD-L1 and LGALS9 can exhaust T-cells, reducing their effectiveness. Studies have shown that treating tumors with anti-IFN-β antibodies helps block PD-L1, improving tumor destruction.
CD8 T-cells with increased IFN-I gene activity experience mitochondrial damage, reducing their viability and effectiveness. These changes are associated with systemic lupus erythematosus (SLE) development. Disrupted programmed cell death processes can either enhance or weaken the clearance of cellular debris, affecting interferon production. In SLE patients, these processes lead to mitochondrial changes in CD8 T-cells, reducing their energy for function and causing cell death, contributing to autoimmune tissue damage.
Regulatory T-Cells (Treg)
Regulatory T-cells are crucial for limiting immune responses and preventing autoimmune diseases. However, excessive Treg activity can reduce the immune response to viruses and cancer cells.
IFN-I regulates Treg functions, reducing their immunosuppressive capability during viral infections and cancer. A lack of IFN-I signals enhances Treg function, promoting tumor growth and reducing the effectiveness of anti-tumor T-cells. Viral infections that cause high levels of IFN can also influence the immune system, either boosting or suppressing its activity, depending on the context.
Macrophages and Myeloid-Derived Suppressor Cells (MDSCs)
Approximately 50% of the cells in the tumor microenvironment are myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and neutrophils. These cells promote tumor development by releasing substances that suppress the immune system and cause persistent tumor inflammation. The protein IRF4 (interferon regulatory factor 4) is associated with anti-inflammatory macrophages that support tumor growth.
Activation of the cGAS/STING signaling pathway is necessary for adequate immune protection against cancer. Mitochondrial DNA activates the cGAS/STING pathway, triggering an anti-tumor immune response and interferon production. IFN-I inhibits the formation of new blood vessels, which supports tumor growth.
Neutrophils and Granulocytic MDSCs (G-MDSCs)
In the tumor microenvironment, inflammatory cytokines IL-1, IL-6, and PGE2 help MDSCs develop and suppress immunity, promoting tumor growth. MDSCs and G-MDSCs populate the tumor microenvironment, with G-MDSCs typically making up 70 to 80% of the cells.
Neutrophils come in two types: N1, which fights the tumor, and N2, which helps it grow. IFN-β activates N1, while TGF-β promotes N2 development.
IFN-I is essential for neutrophil maturation and control over MDSCs, reducing their ability to support the tumor. When IFN-I levels decrease, the PI3K-Akt-mTOR signaling pathway activates, promoting tumor growth.
B-Cells
B-cells, which produce antibodies, play a significant role in protecting against viruses and tumors. IFN-I helps activate B-cells, making them more effective, which increases the expression of specific molecules, leading to more robust B-cell activation. IFN-I also promotes antibody production both in vitro and in vivo. Mice lacking IFN-I receptors on B-cells show reduced antibody responses compared to normal mice.
Activated macrophages and dendritic cells produce IFN-I and IL-12, which help activate NK cells. In turn, NK cells produce IFN-γ, which increases antibody production by B-cells.
IFN-γ also influences B-cell function depending on their state. Activated B-cells can destroy tumor cells, making B-cell vaccines a promising direction in cancer therapy.
Conclusion
Type I interferons are vital in combating tumors and enhancing anti-cancer immunity. Early reduction of IFN-I signals contributes to tumor growth and progression.
High levels of IFN-I are associated with the activation of immune cells to destroy tumors. However, if the IFN-I level in the tumor microenvironment remains low, it can promote tumor growth.
The challenge for scientists is understanding in which context IFN-I works most effectively as an anti-cancer agent. Finding the optimal approach to using IFN-I is vital to successful cancer therapy.
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Reference
Interferons in Immune Cells: Disease Consequences
