期刊
HEPATOLOGY
卷 75, 期 2, 页码 297-308出版社
WILEY
DOI: 10.1002/hep.32150
关键词
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资金
- Ira Schneider Memorial Cancer Research Foundation
- Linda A. Blum Fund for Cholangiocarcinoma Research, and Cancer Kicks
- Translational Molecular Pathology-Immunoprofiling lab (TMP-IL) at the Department of Translational Molecular Pathology
- University of Texas MD Anderson Cancer Center
- OCRA Collaborative Research Development Award
- ICI Fund Award
- NIH/NCI [CPRIT RP170640]
This study integrated immunohistochemistry with next-generation sequencing to analyze intrahepatic CCA samples and found that T-cell and immune checkpoint markers were enriched at tumor margins compared to the center. High PD-1 or LAG-3 and low CD3/CD4/ICOS in the tumor center were associated with poor survival. Loss-of-function mutations in BRCA1-associated protein-1 were associated with elevated expression of the immunosuppressive checkpoint marker B7-H4.
Background and Aims Cholangiocarcinoma (CCA) is a deadly and highly therapy-refractory cancer of the bile ducts, with early results from immune checkpoint blockade trials showing limited responses. Whereas recent molecular assessments have made bulk characterizations of immune profiles and their genomic correlates, spatial assessments may reveal actionable insights. Approach and Results Here, we have integrated immune checkpoint-directed immunohistochemistry with next-generation sequencing of resected intrahepatic CCA samples from 96 patients. We found that both T-cell and immune checkpoint markers are enriched at the tumor margins compared to the tumor center. Using two approaches, we identify high programmed cell death protein 1 or lymphocyte-activation gene 3 and low CD3/CD4/inducible T-cell costimulator specifically in the tumor center as associated with poor survival. Moreover, loss-of-function BRCA1-associated protein-1 mutations are associated with and cause elevated expression of the immunosuppressive checkpoint marker, B7 homolog 4. Conclusions This study provides a foundation on which to rationally improve and tailor immunotherapy approaches for this difficult-to-treat disease.
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