Tumor stage-driven disruption of NK cell maturation in human and murine tumors

• DOI: 10.1016/j.isci.2024.111233
• Publication Date: 2024-10-23T16:51:06Z
• Authors: Jules Russick; Carine Torset; Dan Sun; Solenne Marmier; Nicolas Merle; Elodie Voilin; Nathalie Josseaume; Maxime Meylan; Isaïas Hernandez; Pierre-Emmanuel Foy; Pierre-Emmanuel J...; Marco Alifano; Audrey Lupo; Sophie Siberil; Niklas K. Björkström; Diane Damotte; Isabelle Cremer
• Keywords: 0303 health sciences; Cancer systems biology; maturation; Science; Immunology; Q; 610; NK cells; NK dysfunction; single-cell sequencing; Article; [SDV] Life Sciences [q-bio]; lung cancer; Biological sciences; 03 medical and health sciences; pseudotime; Natural sciences; tumor microenvironment; cytotoxicity; Systems biology; NK exclusion; Cancer

Natural killer (NK) cells play a pivotal role against cancer, both by direct killing of malignant cells and by promoting adaptive immune response though cytokine and chemokine secretion. In the lung tumor microenvironment (TME), NK cells are scarce and dysfunctional. By conducting single-cell transcriptomic analysis of lung tumors, and exploring pseudotime, we uncovered that the intratumoral maturation trajectory of NK cells is disrupted in a tumor stage-dependent manner, ultimately resulting in the selective exclusion of the cytotoxic subset. Using functional assays, we observed intratumoral NK cell death and a reduction in cytotoxic capacities depending on the tumor stage. Finally, our analyses of human public dataset on lung cancer corroborate these findings, revealing a parallel dysfunctional maturation process of NK cells during tumor progression. These results highlight additional mechanisms by which tumor cells escape from NK cell cytotoxicity, therefore paving the way for tailored therapeutic strategies.