Generation of Cytokine-Induced Memory-Like NK Cells derived from hiPSCs for Immunotherapy Applications

• Grant number: 25/05497-8
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: June 30, 2025
• End date: December 29, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Rodrigo Nalio Ramos
• Grantee: Maria Paula Oliveira Lima
• Supervisor: Fernando de Souza Fonseca Guimaraes
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Queensland, Brisbane (UQ), Australia
• Associated to the scholarship: 24/03044-3 - Generation of CAR-NK Memory-Like NKG2A KO cells using CRISPR-Cas9, BP.MS

Abstract

Natural Killer (NK) cells are critical components of the innate immune system, recognized for their ability to eliminate tumor cells. However, the limited availability, donor variability, and genetic modification challenges associated with primary NK cells restrict their widespread application in immunotherapy. To overcome these limitations, human induced pluripotent stem cells (hiPSCs) have emerged as a promising alternative for generating off-the-shelf NK cells for cell therapy applications, providing an unlimited, standardized, and genetically modifiable source. Unlike primary NK cells, iPSCs are highly permissive to genetic modification via viral vectors, RNA, or plasmid transfection, making them an ideal platform for engineered NK cell therapies. In close collaboration with Professor Guimaraes' group at Frazer Institute in Australia, this project aims to develop NK cells differentiated from hiPSCs (iNK) through a two-step approach: (1) induce cytokine-induced memory-like NK (CIML NK) properties in iNK cells and in peripheral blood primary CIML NK cells, and (2) Conduct a detailed comparison of their phenotypic and functional potential. The resulting iNK cells will be evaluated alongside CIML NKs, comparing phenotypic markers, degranulation capacity, cytokine production (IFN-¿, TNF-¿), and cytotoxicity against tumor cells in vitro. Beyond scientific advancements, this project will establish a new international collaboration with a leading NK cell research group. The expected outcomes include the successful differentiation of functionally competent iNK cells, with comparable or superior anti-tumor activity to primary CIML NK cells, paving the way for enhanced immunotherapies based on NK cells for tumor control.