Format

Send to

Choose Destination
Cancer Discov. 2017 Dec;7(12):1420-1435. doi: 10.1158/2159-8290.CD-17-0593. Epub 2017 Oct 12.

Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer.

Author information

1
Department of Medicine (Section of Medical Oncology), Yale University School of Medicine, New Haven, Connecticut. katerina.politi@yale.edu scott.gettinger@yale.edu.
2
Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
3
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
4
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
5
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut.
6
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut.
7
Department of Medicine (Section of Medical Oncology), Yale University School of Medicine, New Haven, Connecticut.
8
CIMA and Clinica Universidad de Navarra, Pamplona, Spain.
9
Centro de Investigación Biomédica en red de Oncología CIBERONC, Madrid, Spain.
10
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
11
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut.

Abstract

Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.Significance: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer. Cancer Discov; 7(12); 1420-35. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.

PMID:
29025772
PMCID:
PMC5718941
DOI:
10.1158/2159-8290.CD-17-0593
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center