In a newly published paper, scientists provide evidence that cancer secretes micro-particles (exosomes) which dampens immune response to viral infection.
The immune system recognizes different molecules on viral particles through series of pathogen-associated molecular pattern recognition sequences (PAMPS) expressing on various innate immune cells. These cells initiate a series of signaling upon activation of PAMPS after binding with viral particles. Activation ultimately leads to the production of the potent antiviral molecules, type I interferons, and various inflammatory cytokines providing an excellent immune response to viral infection. Modulation of the immune response can be caused by specific disease and condition such as malignancy of cancer, transplantation, infection, chemotherapy, systemic vasculitis and connective tissue disease. These modulations can have far-reaching repercussion on the outcome of infection and may leave humans susceptible to pathogens.
It is a well-known fact that cancer reduces the immune response in its microenvironment to escape antitumor activity. Recent studies even provided evidence that tumor cells secrete immunomodulatory molecules within exosomes (membrane-enclosed small vesicles). These exosomes are called tumor-derived exosomes (TEX) and can be transferred horizontally across the body to carry functional biomolecules such as proteins, lipids, DNA and RNA. TEX has been shown to be the regulator of tumorigenesis and impart the indirect effect on the immune system to provide tumor growth and metastasis. However, TEX effect on viral immune response has not been shown until now. The team provides that data for the first time that TEX can carry a biomolecule to macrophages to reduce its ability to produce type I interferon, an essential protein in antivirus immune response.
In this study, authors first found a clinical relevant data where lung cancer patients had a lower level of serum interferon-beta in response to flu infection than people without cancer. To investigate further, authors conducted series of in-vitro and in-vivo experiments in animal models to delineate the relevance and mechanism of this clinical finding further. They found that TEX produced by cancer cells contained a protein, epidermal growth factor receptor (EGFR), which could be transferred to innate immune cells such as macrophages. These macrophages could not produce enough type I interferon in response to virus infection upon encountering EGFR loaded exosomes. Scientists further wanted to know how EGFR exposure in macrophages leads to reduced anti-viral protein. They found that EGFR induced expression of MEKK2, a type of kinase protein, which ultimately caused deregulation of interferon production. The mechanism by which MEKK2 imparts this effect in macrophages was further investigated and found to induce phosphorylation of a transcription factor IRF-3 at a serine173 position in MEKK2 dependent manner. IRF-3 is a critical transcription factor for production of type-I interferon, once activated it localizes into the nucleus of the cells, where it binds to the DNA of interferon gene and thus leading to its production. MEKK3 induced IRF-3 phosphorylation led to k33 linked poly-ubiquitination at a specific site of IRF-3 causing interference in its translocation into the nucleus of the cells and thus resulting in reduced expression of interferon genes.
Many recent studies have shown that exosomes produced by tumors can modulate the immune response to give cancer cells a survival, propagation and metastatic advantage. However, this is the first time; a detailed mechanistic study provides evidence for reduced antiviral immune response among cancer patients.