With the remarkable results of cancer immunotherapy using immune checkpoint inhibitors, the possibility of treatment using the immune response is highly expected. On the other hand, they release the brakes on immunity and strengthen the immune system in a “non-specific” manner. Therefore, the development of novel drugs that enhance immunity in a “cancer-specific” manner is required. On the other hand, many autoimmune diseases are treated with steroids or immunosuppressive drugs, but these “nonspecifically” suppress the entire immune system, causing side effects such as opportunistic infections. Therefore, there is a need to develop a method to “specifically” suppress self-reactive cells. As mentioned above, the development of drugs that take advantage of the “specificity” of immunity is expected to lead to the development of innovative treatments, but this has not yet been achieved. Therefore, we will develop innovative immuno-regulatory drugs with this “specificity” by artificially engineering extracellular vesicles called exosomes.
Exosomes are extracellular vesicles of about 30-100 nm in diameter secreted by most cell types. They carry proteins, lipids, and RNAs derived from the secretory cells, and serve as a novel intercellular communicator that controls various functions. (Fig. 1). In particular, molecules that activate the immune system (such as antigen-MHC complex) are present on exosomes secreted by immune cells, whereas molecules that suppress the immune system (Fas-L and PD-L1) are present on exosomes secreted by cancer cells, regulating various vital phenomena such as the control of immune response and cancer progression through these immune regulatory molecules. For this reason, drug discovery targeting exosomes or using exosomes is highly expected at present.
In particular, by producing chimeric molecules with tetraspanins (such as CD9, CD63, CD81), which are surface markers of exosomes, it has become possible to express the proteins of interest on exosomes. Thus, we are developing engineered exosomes that control the immune system by producing chimeric molecules of various immuno-regulatory proteins and tetraspanins to be expressed on exosomes. Therefore, in this research, by applying this technique to develop a technology that allows simultaneous expression of multiple immuno-regulatory molecules on exosomes, we will realize “innovative immuno-regulation methods” that cannot be realized by simple individual combinations. In other words, efficient activation of immune cells requires signals from multiple immuno-regulatory molecules simultaneously, but they disperse in vivo with conventional immuno-regulation methods (Fig. 2). As a result, it causes not only inefficient activation of target immune cells but also “non-specific” activation of non-target immune cells causing various side effects. On the other hand, by using our technology, multiple immuno-regulatory molecules are simultaneously transported in vivo via exosomes and used in the same place, causing synergistic effects for “specific” activation of target immune cells, which cannot be achieved by a simple combination of individual immuno-regulatory molecules.
By developing engineered exosomes with enhanced immuno-regulatory functions, we will develop methods to generate “immune cells that specifically attack only cancer cells” and “immune cells that specifically suppress autoimmunity/allergy” in the patients. Through this, we aim to develop treatments that are efficient and have few side effects for these diseases.
Figure 1: Molecules on exosomes.Exosomes carry various immune regulatory molecules. In particular, tetraspanins are well-known surface exosomal markers. By producing a chimeric molecule with tetraspanins, it is possible to express any target protein on exosomes.
Figure 2: Goal of our research.By developing a technology to simultaneously express multiple immuno-regulatory molecules (Signal 1,2,3) on exosomes, we aim to realize “innovative immuno-regulatory methods” that cannot be achieved by simple individual combinations (in this case, only orange T cells are specifically activated).
Figure 3: Group photo of Hanayama laboratory.