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Nat Commun. 2017 Oct 26;8(1):1136. doi: 10.1038/s41467-017-01062-w.

Resistance to checkpoint blockade therapy through inactivation of antigen presentation.

Author information

1
Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, 02114, USA.
2
Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA.
3
Department Systems Biology, Harvard Medical School, Boston, MA, 02115, USA.
4
Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
6
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
7
Department of Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA.
8
New York Genome Center, NYC, New York, NY, 10013, USA.
9
Department of Medicine and Department of Physiology and Biophysics, Weill Cornell Medicine, NYC, New York, NY, 10065, USA.
10
Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, 02114, USA. RSULLIVAN7@mgh.harvard.edu.
11
Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, 02114, USA. NHACOHEN@mgh.harvard.edu.
12
Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA. NHACOHEN@mgh.harvard.edu.

Abstract

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

PMID:
29070816
PMCID:
PMC5656607
DOI:
10.1038/s41467-017-01062-w
[Indexed for MEDLINE]
Free PMC Article

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