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.
Author Info: (1) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Ho
Author Info: (1) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (2) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (3) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (4) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA. (5) MicRoN Core, Harvard Medical School, Boston, MA, USA. (6) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (7) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (8) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (9) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (10) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (11) Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (12) MicRoN Core, Harvard Medical School, Boston, MA, USA. (13) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. (14) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Brain and Cognitive Science, MIT, Cambridge, MA, USA. Department of Biological Engineering, MIT, Cambridge, MA, USA. McGovern Institute for Brain Research at MIT, Cambridge, MA, USA. Howard Hughes Medical Institute, MIT, Cambridge, MA, USA. (15) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (16) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (17) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (18) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Biology and Koch Institute of Integrative Cancer Research, MIT, Cambridge, MA, USA. Genentech, South San Francisco, CA, USA. (19) Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. (20) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. mvmaus@mgh.harvard.edu. Harvard Medical School, Boston, MA, USA. mvmaus@mgh.harvard.edu. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. mvmaus@mgh.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. mvmaus@mgh.harvard.edu.
