Radiation and Acquired Immunity: The Role of NK Cells

Trained immunity describes the immunological process by which innate immune cells acquire immunological memory. Following exposure to specific stimuli, the myeloid lineage cells undergo epigenetic reprogramming, which results in long-term changes in their metabolic and phenotypic behavior that enables a stronger immune response to secondary stimuli. One of these types of cells that form in the process of trained immunity are also memory-like natural killer (mNK) cells. Due to their prolonged activation and high cytotoxicity, mNKceIIs are gaining attention in the field ofimmunotherapy for solid tumors. In clinical trials, NK cell-based therapy is being combined with radiotherapy to enhance the antitumor effect of mNK cells. Although irradiation is known to affect innate and acquired immune cells, it is not clear whether irradiation can induce acquired immunity and the formation of mNK cells. The main problem addressed in this project is to answer the question: "Does irradiation of tumors induce memory-like natural killer cell population?" To answer this question, we will irradiate mouse tumors with clinically relevant doses of single and fractionated irradiation and determine the effect of irradiation on NK cell populations after treatment. The aim of our proposed project is to investigate the impact of different irradiation regimes on NK cells in mouse models of colon cancer CT26 and breast cancer 4Tl. We will determine the antitumor effect of radiation regimes and how they affect the infiltration of NK cells in tumors. The radiation regime that causes the greatest infiltration of NK cells in tumors will be used in further experiments to determine whether radiation can induce the formation of mNK cells in lymphoid organs, as well as the impact of radiation on gene expression in mNK cells. Finally, we will evaluate the functional properties of irradiation-induced mNK cells by assessing their migration and cytotoxicity against tumor cells in uitro and in vivo. Understanding the effects of radiation on NK cell populations will aid in designing combination therapies that combine radiotherapy and NK cell-based therapies, which are gaining momentum in the treatment of solid tumors.