Tsao, Anderson, and Finn et al. demonstrated that loss of endoplasmic reticulum aminopeptidase (ERAP), which trims peptides for presentation on MHC class I, sensitized mouse tumor models to immune surveillance. In vivo, screens revealed that ERAP-mediated N-terminal trimming generated the restricted set of invariant epitopes (VL9) presented on HLA-E/Qa-1b (HLA-E), which was required to maintain the HLA-E-NKG2A checkpoint. ERAP deletion altered the HLA-E peptidome and disrupted the HLA-E–NKG2A checkpoint, increasing CD8+ T and NK cell-mediated killing. In human cells, loss of ERAP1/2 in tumors increased their susceptibility to ICB in vitro and in vivo.
Contributed by Shishir Pant
ABSTRACT: The aminopeptidase, endoplasmic reticulum aminopeptidase 1 (ERAP1), trims peptides for loading into major histocompatibility complex class I (MHC class I), and loss of this activity has broad effects on the MHC class I peptidome. Here, we investigated the impact of targeting ERAP1 in immune checkpoint blockade (ICB), as MHC class I interactions mediate both activating and inhibitory functions in antitumor immunity. Loss of ERAP sensitized mouse tumor models to ICB, and this sensitivity depended on CD8(+) T cells and natural killer (NK) cells. In vivo suppression screens revealed that Erap1 deletion inactivated the inhibitory NKG2A-HLA-E checkpoint, which requires presentation of a restricted set of invariant epitopes (VL9) on HLA-E. Loss of ERAP altered the HLA-E peptidome, preventing NKG2A engagement. In humans, ERAP1 and ERAP2 showed functional redundancy for the processing and presentation of VL9, and loss of both inactivated the NKG2A checkpoint in cancer cells. Thus, loss of ERAP phenocopies the inhibition of the NKG2A-HLA-E pathway and represents an attractive approach to inhibit this critical checkpoint.
Author Info: (1) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (2) Broad
Author Info: (1) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (2) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (3) Calico Life Sciences, South San Francisco, CA, USA. (4) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (5) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (6) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (7) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (8) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (9) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (10) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (11) Calico Life Sciences, South San Francisco, CA, USA. (12) Calico Life Sciences, South San Francisco, CA, USA. (13) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. (14) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. (15) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. (16) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. (17) Calico Life Sciences, South San Francisco, CA, USA. (18) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (19) Calico Life Sciences, South San Francisco, CA, USA. (20) Calico Life Sciences, South San Francisco, CA, USA. (21) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (22) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (23) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (24) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (25) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (26) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (27) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (28) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (29) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (30) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (31) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (32) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (33) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (34) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (35) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (36) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (37) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. (38) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. (39) Calico Life Sciences, South San Francisco, CA, USA. (40) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. (41) Calico Life Sciences, South San Francisco, CA, USA. (42) Calico Life Sciences, South San Francisco, CA, USA. (43) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. (44) Calico Life Sciences, South San Francisco, CA, USA. Electronic address: fah@calicolabs.com. (45) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Electronic address: yates@broadinstitute.org. (46) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Electronic address: rmanguso@broadinstitute.org.
