Larson et al. conducted a genome-wide CRISPR knockout screen in a glioblastoma cell line, and identified that loss of interferon-γ receptor (IFNγR) signaling pathway genes (IFNGR1, JAK1 or JAK2) conferred resistance to CAR T cell killing. IFNγR1 blockade/IFNγR1-KO and JAK2-KO showed resistance to CAR T cells in several solid tumors, but not in hematologic malignancies, in a CAR T target-independent manner. Loss of IFNγR1 in glioblastoma cells downregulated ICAM1 expression and reduced CAR T cell–tumor cell binding duration and avidity. Antibody-mediated blockade of ICAM-1 increased resistance to CAR T cell killing in solid tumors.
Contributed by Shishir Pant
ABSTRACT: Chimeric antigen receptor (CAR) therapy has had a transformative effect on the treatment of haematologic malignancies1-6, 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 efficacy7,8. We found that the loss of genes in the interferon-γ receptor (IFNγR) 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 IFNγR1 had lower upregulation of cell-adhesion pathways after exposure to CAR T cells. We found that loss of IFNγR1 in glioblastoma cells reduced overall CAR T cell binding duration and avidity. The critical role of IFNγR 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, IFNγR 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.