By performing genome-scale in vivo CRISPR KO screens across eight ICB-treated mouse models of five cancer types, Dubrot and Du et al. identified shared and context-specific mechanisms of antitumor and ICB-mediated immunity. Tumor response to ICB was centrally regulated by the IFN signaling pathway and antigen presenting genes. Screening data, TCGA and RNAseq analyses, and mouse models showed that tumor IFN sensing inhibits NK cells and CD8+ T/CAR T cells via classical and non-classical (Qa-1b) MHC-I upregulation, respectively. Strong IFN signatures in pretreatment RCC and melanoma biopsies associated in opposite ways with ICB response.
Contributed by Paula Hochman
ABSTRACT: The immune system can eliminate tumors, but checkpoints enable immune escape. Here, we identify immune evasion mechanisms using genome-scale in vivo CRISPR screens across cancer models treated with immune checkpoint blockade (ICB). We identify immune evasion genes and important immune inhibitory checkpoints conserved across cancers, including the non-classical major histocompatibility complex class I (MHC class I) molecule Qa-1b/HLA-E. Surprisingly, loss of tumor interferon-γ (IFNγ) signaling sensitizes many models to immunity. The immune inhibitory effects of tumor IFN sensing are mediated through two mechanisms. First, tumor upregulation of classical MHC class I inhibits natural killer cells. Second, IFN-induced expression of Qa-1b inhibits CD8+ T cells via the NKG2A/CD94 receptor, which is induced by ICB. Finally, we show that strong IFN signatures are associated with poor response to ICB in individuals with renal cell carcinoma or melanoma. This study reveals that IFN-mediated upregulation of classical and non-classical MHC class I inhibitory checkpoints can facilitate immune escape.
Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Massachusetts Gener
Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. (2) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Stanford University School of Medicine, Stanford, CA, USA. (3) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (4) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (5) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (7) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (8) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (9) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (10) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (11) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (12) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (13) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (14) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (15) Broad Institute of MIT and Harvard, Cambridge, 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. (19) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (20) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (21) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (22) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (23) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (24) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (25) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (26) Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (27) Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (28) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. ArsenalBio, South San Francisco, CA, USA. (29) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (30) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (31) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (32) Broad Institute of MIT and Harvard, Cambridge, MA, USA. yates@broadinstitute.org. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. yates@broadinstitute.org. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. yates@broadinstitute.org. (33) Broad Institute of MIT and Harvard, Cambridge, MA, USA. rmanguso@mgh.harvard.edu. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. rmanguso@mgh.harvard.edu. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. rmanguso@mgh.harvard.edu.
