CAR T cell killing requires the IFN gamma R pathway in solid but not liquid tumours

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-gamma receptor (IFN gamma 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 gamma R1 had lower upregulation of cell-adhesion pathways after exposure to CAR T cells. We found that loss of IFN gamma R1 in glioblastoma cells reduced overall CAR T cell binding duration and avidity. The critical role of IFN gamma 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 gamma 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.

Automated summary

CAR T cell therapy has shown limited efficacy against solid tumours, and this study identifies the loss of genes in the interferon-gamma receptor signalling pathway as a potential resistance mechanism in glioblastoma and other solid tumours. The study reveals that the interferon-gamma receptor signalling pathway is critical for the adhesion and cytotoxicity of CAR T cells in solid tumours, highlighting the importance of enhancing binding interactions between T cells and tumour cells for improved responses in solid tumours.