BASIC DATA OF THE RESEARCH PROJECT
- ARRS code: Z3-50112
- TITLE: Irradioation and learned immunity: The role of NK cells
- PRICE CLASS: B
- PROJECT LEADER: Tim Božič, PhD
- APPLICANT RESEARCH ORGANISATION: INSTITUTE OF ONCOLOGY LJUBLJANA
- DURATION: 1.10.2023 – 30.9.2025
- FINANCING: Slovenian Research and Innovation Agency
- Irradiation and trained 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 [2]. Although this phenomenon has been studied mainly after infections with pathogens and after vaccination, there is growing evidence that trained immunity also plays a role in cancer. One of the first indications, which also served as the basis for the discovery of trained immunity, was the Bacillus Calmette–Guérin (BCG) vaccination against tuberculosis, which is today a US Food and Drug Administration-approved treatment modality for bladder cancer, and other malignancies such as lymphoma and melanoma. One of these type 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, mNK cells are gaining attention in the field of immunotherapy for solid tumors. In clinical trials, NK cell-based therapy is being combined with radiotherapy to enhance the antitumor effect of mNK cells. Previous studies have shown different effects of irradiation on NK cells. Although irradiation is known to affect both innate and acquired immune cells, it is not clear whether irradiation can induce acquired immunity and the formation of mNK cell populations. 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 4T1. We will determine the antitumor effect of clinically relevant 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 vitro and in vivo. Understanding the effects of radiation on NK cell populations in the tumor microenvironment will not only help to determine optimal irradiation parameters but also aid in designing combination therapies that combine radiotherapy and NK cell-based therapies, which are gaining momentum in the treatment of solid tumors.