Ph.D. Student The Chinese University of Hong Kong (CUHK) Hong Kong, Hong Kong
Abstract: Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Although immune checkpoint inhibitor (ICI) therapies have significantly improved survival outcomes in advanced NSCLC, up to 85% of patients develop treatment resistance. The immunosuppressive tumour microenvironment (TME) is believed to play a significant role in the development of ICI resistance. Genetically engineered mesenchymal stem cell (MSC) therapy represents a promising approach for cancer treatment due to its low immunogenicity, tumoritropic nature, cost effectiveness and potential availability as an “off-the-shelf” therapy. In this study, we present IL-24-iMSC, a novel therapeutic in which MSCs are genetically modified to secrete interleukin 24 (IL-24), an immunomodulatory cytokine with anti-cancer properties. Using CRISPR/Cas9, the IL-24 gene was inserted into induced mesenchymal stem cells (iMSCs) at the B2M locus, with expression driven by the EF1α promoter. Flow cytometry revealed high expression of MSC surface markers (CD73, CD90, CD105) and absence of hematopoietic (CD34, CD45) and HLA-DR markers, confirming the MSC phenotype. Enzyme-linked immunosorbent assay (ELISA) demonstrated sustained IL-24 secretion from IL-24-iMSCs, while control iMSCs showed no IL-24 production. Tumour tropism of IL-24-iMSC was validated in xenograft models, where infiltration of stem cells into tumours was observed. Future investigations will focus on evaluating the immunomodulatory effects of IL-24-iMSC in orthotopic models using immunocompetent mice. This study aims to provide preclinical evidence supporting the development of IL-24-iMSC as a therapeutic strategy for NSCLC. Furthermore, it will offer critical insights into the potential of genetically engineered stem cell therapy to enhance immunotherapy outcomes in lung cancer patients.
