Research into the effect of an arginase-1 inhibitor on the development of an antigen-specific immune response in lymph nodes

In recent years, cancer immunotherapy has become an effective method of cancer treatment, leading to complete remission of the disease in 20-30% of cases. Nevertheless, this therapy is still ineffective in many patients and the mechanisms of resistance to immunotherapy are being searched for. One such potential mechanism may be the activity of arginase, the enzyme that breaks down L-arginine. The reduced concentration of arginine in the tumor microenvironment or in the lymph nodes draining the tumor area inhibits lymphocyte proliferation by reducing the expression of the CD3Z and CD3s chains, which are components of the T lymphocyte receptor complex (TCR) used for antigen recognition. Our preliminary research indicates that arginase inhibits T cell proliferation, and an arginase inhibitor, developed in collaboration with our team, reverses the suppressive effect of arginase on lymphocytes under cell culture conditions. The main scientific task of the project is to study the effects of arginase inhibitors on the development of antigen-specific T cell immune responses in a completely new research model using transparent lymphoid organs. For this purpose, a method will be developed to obtain transparent lymph nodes, which will enable their quick, microscopic imaging in full, in a natural three-dimensional state. The use of antigen-specific T lymphocytes isolated from double transgenic mice in which the constitutive expression of the DsRed fluorescent protein is used in the research will allow for the localization and creation of a spatial distribution map of all lymphocytes within the entire lymph node, not cut into histological sections. The implementation of the project assumptions will contribute to the development of a lymph node 'transparency' protocol, which does not damage their microscopic structure or degrade fluorescent proteins. The new method may in the future help to solve many research problems, currently limited by the need to image only tissue sections. It is expected that the application of the described novel research model will provide a precise description of the immunostimulatory effect of the arginase-1 inhibitor on the cellular response of T lymphocytes. This result may constitute an important argument justifying attempts to include compounds of this class in clinical trials in combination with cancer immunotherapy.