Fernando Carapeto1, Behnaz Bozorgui2, Rachna T Shroff3, Sharmeen Chagani1, Luisa Solis Soto1, Wai Chin Foo4, Ignacio Wistuba1, Funda Meric-Bernstam5, Ahmed Shalaby6, Milind Javle6, Anil Korkut2, Lawrence N Kwong1,7. 1. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 2. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 3. Department of Medicine, University of Arizona Cancer Center, Tucson, Arizona, USA. 4. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 5. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 6. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 7. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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.
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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