Cortisol-resistant Chimeric Antigen Receptor (CAR)-NK cells overcome steroid-induced immunosuppression in lung cancer 9085

Abstract Description Tumour microenvironments (TME) accumulate immunosuppressive steroids, impairing NK cell anti-tumour immunity. We found glucocorticoid cortisol signalling enrichment in lung TME exacerbates hypoxic stress and impairs NK cell function. Single-cell transcriptomics revealed cancer-associated fibroblasts and macrophages convert inactive cortisone to active cortisol, while T cells, mast cells, and macrophages induce de novo steroid biosynthesis. Inhibiting the glucocorticoid receptor in mice reduced tumour growth and improved NK cell cytotoxicity.To overcome steroid-mediated immunosuppression, we engineered CEACAM5-specific CAR-NK cells with CRISPR-mediated deletion of the glucocorticoid receptor (NR3C1). These cortisol-resistant CAR-NK cells showed enhanced tumour cell killing efficacy, even in the presence of glucocorticoids. This approach offers promising applications against steroidogenic solid tumours and potential use alongside therapeutic glucocorticoids. Our study addresses a critical challenge in CAR-NK cell therapy for lung cancer - the immunosuppressive TME. By targeting CEACAM5, highly expressed in lung tumours, and making CAR-NK cells cortisol-resistant, we’ve developed a novel strategy to enhance the efficacy of immunotherapy in steroid-rich environments. This advancement could significantly improve outcomes for lung cancer patients, addressing limitations of current CAR-NK therapies in solid tumours. Funding Sources The work is supported by CRUK Career Development Fellowship (RCCFEL\100095), NSF-BIO/UKRI-BBSRC project grant (BB/V006126/1), MRC project grant (MR/V028995/1), CRUK Cambridge Centre Cancer Immunology Programme Pump Priming award, and CRUK CC MRes/PhD Studentship. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)