CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours

Rebecca C. Larson, Michael C. Kann, Stefanie R. Bailey, Nicholas J. Haradhvala, Paula Montero Llopis, Amanda A. Bouffard, Irene Scarfó, Mark B. Leick, Korneel Grauwet, Trisha R. Berger, Kai Stewart, Praju Vikas Anekal, Max Jan, Julia Joung, Andrea Schmidts, Tamara Ouspenskaia, Travis Law, Aviv Regev, Gad Getz and Marcela V. Maus ()
Additional contact information
Rebecca C. Larson: Massachusetts General Hospital
Michael C. Kann: Massachusetts General Hospital
Stefanie R. Bailey: Massachusetts General Hospital
Nicholas J. Haradhvala: Broad Institute of MIT and Harvard
Paula Montero Llopis: Harvard Medical School
Amanda A. Bouffard: Massachusetts General Hospital
Irene Scarfó: Massachusetts General Hospital
Mark B. Leick: Massachusetts General Hospital
Korneel Grauwet: Massachusetts General Hospital
Trisha R. Berger: Massachusetts General Hospital
Kai Stewart: Massachusetts General Hospital
Praju Vikas Anekal: Harvard Medical School
Max Jan: Massachusetts General Hospital
Julia Joung: Broad Institute of MIT and Harvard
Andrea Schmidts: Massachusetts General Hospital
Tamara Ouspenskaia: Broad Institute of MIT and Harvard
Travis Law: Broad Institute of MIT and Harvard
Aviv Regev: Broad Institute of MIT and Harvard
Gad Getz: Harvard Medical School
Marcela V. Maus: Massachusetts General Hospital

Nature, 2022, vol. 604, issue 7906, 563-570

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04585-5

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