The immunogenomic landscape of resected intrahepatic cholangiocarcinoma

Fernando Carapeto; Behnaz Bozorgui; Rachna T Shroff; Sharmeen Chagani; Luisa Solis Soto; Wai Chin Foo; Ignacio Wistuba; Funda Meric-Bernstam; Ahmed Shalaby; Milind Javle; Anil Korkut; Lawrence N Kwong

doi:10.1002/hep.32150

The immunogenomic landscape of resected intrahepatic cholangiocarcinoma

Hepatology. 2022 Feb;75(2):297-308. doi: 10.1002/hep.32150. Epub 2021 Dec 6.

Authors

Affiliations

¹ Department of Translational Molecular PathologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA.
² Department of Bioinformatics and Computational BiologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA.
³ Department of MedicineUniversity of Arizona Cancer CenterTucsonArizonaUSA.
⁴ Department of PathologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA.
⁵ Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA.
⁶ Department of Gastrointestinal Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA.
⁷ Department of Genomic MedicineThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Aged
Aged, 80 and over
Antigens, CD / genetics
Antigens, CD / metabolism*
B7 Antigens / genetics
Bile Duct Neoplasms / genetics*
Bile Duct Neoplasms / immunology
Bile Duct Neoplasms / metabolism*
Bile Ducts, Intrahepatic
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
CD4-Positive T-Lymphocytes
Cell Line, Tumor
Cholangiocarcinoma / genetics*
Cholangiocarcinoma / immunology
Cholangiocarcinoma / metabolism*
Female
Gene Expression
Genes, Tumor Suppressor
Genomics
High-Throughput Nucleotide Sequencing
Humans
Immunohistochemistry
Inducible T-Cell Co-Stimulator Protein / genetics
Inducible T-Cell Co-Stimulator Protein / metabolism
Loss of Function Mutation
Lymphocyte Activation Gene 3 Protein
Male
Middle Aged
Oncogenes / genetics
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / metabolism*
Survival Rate
Tumor Suppressor Proteins / genetics
Ubiquitin Thiolesterase / genetics
V-Set Domain-Containing T-Cell Activation Inhibitor 1 / genetics
Young Adult

Substances

Antigens, CD
B7 Antigens
BAP1 protein, human
Biomarkers, Tumor
CD276 protein, human
Inducible T-Cell Co-Stimulator Protein
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Tumor Suppressor Proteins
V-Set Domain-Containing T-Cell Activation Inhibitor 1
VTCN1 protein, human
Ubiquitin Thiolesterase
Lymphocyte Activation Gene 3 Protein
Lag3 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding