CELL INTELLIGENCE · 肿瘤细胞治疗研究

Chimeric antigen receptor (CAR) therapy has had a transformative effect on the treatment of haematologic malignancies 1-6 , but it has shown limited efficacy against solid tumours. Solid tumours may have cell-intrinsic resistance mechanisms to CAR T cell cytotoxicity. Here, to systematically identify potential resistance pathways in an unbiased manner, we conducted a genome-wide CRISPR knockout screen in glioblastoma, a disease in which CAR T cells have had limited efficacy 7,8 . We found that the loss of genes in the interferon- receptor (IFN R) signalling pathway (IFNGR1, JAK1 or JAK2) rendered glioblastoma and other solid tumours more resistant to killing by CAR T cells both in vitro and in vivo. However, loss of this pathway did not render leukaemia or lymphoma cell lines insensitive to CAR T cells. Using transcriptional profiling, we determined that glioblastoma cells lacking IFN R1 had lower upregulation of cell-adhesion pathways after exposure to CAR T cells. We found that loss of IFN R1 in glioblastoma cells reduced overall CAR T cell binding duration and avidity. The critical role of IFN R signalling in susceptibility of solid tumours to CAR T cells is surprising, given that CAR T cells do not require traditional antigen-presentation pathways. Instead, in glioblastoma tumours, IFN R signalling was required for sufficient adhesion of CAR T cells to mediate productive cytotoxicity. Our work demonstrates that liquid and solid tumours differ in their interactions with CAR T cells and suggests that enhancing binding interactions between T cells and tumour cells may yield improved responses in solid tumours.