Overcoming CXCR4-Mediated T-Cell Exclusion Potentiates Antitumor Cytotoxicity in Fibrolamellar Carcinoma

Authors

• Jason A. Carter, University of Washington, Seattle, WA
• Lindsay K. Dickerson, University of Washington, Seattle, WA
• Andreas Stephanou, Cornell University College of Veterinary Medicine, Ithaca, NY
• Sheela R. Damle, University of Washington, Seattle, WA
• Kristin E. Goodsell, University of Washington, Seattle, WA
• Sara K. Daniel, University of Washington, Seattle, WA
• Kevin M. Sullivan, LSU Health Sciences Center - New OrleansFollow
• Bo Shui, Cornell University College of Veterinary Medicine, Ithaca, NY
• Xiuyun Jiang, University of Washington, Seattle, WA
• Heidi L. Kenerson, University of Washington, Seattle, WA
• Renske J. van den Bijgaart, Fred Hutchinson Cancer Center, Seattle, WA
• Alaa R. Farghli, Cornell University College of Veterinary Medicine, Ithaca, NY
• Yongjun Liu, University of Washington, Seattle, WA
• Emily Beirne, University of Washington, Seattle, WA
• Kevin P. Labadie, University of Washington, Seattle, WA
• Jack Cernak, University of Washington, Seattle, WA
• Sardar Shahmir Chauhan, University of Washington, Seattle, WA
• Jose Mario Bello Pineda, University of Washington, Seattle, WA
• Annalyssa N. Long, Fred Hutchinson Cancer Center, Seattle, WA
• Anna E. Elz, Fred Hutchinson Cancer Center, Seattle, WA
• Evan W. Newell, Fred Hutchinson Cancer Center, Seattle, WA
• Teresa S. Kim, University of Washington, Seattle, WA
• Kimberly J. Riehle, University of Washington, Seattle, WA
• Raymond S. Yeung, University of Washington, Seattle, WA
• Shreeram Akilesh, University of Washington, Seattle, WA
• Ian N. Crispe, University of Washington, Seattle, WA
• Kevin C. Barry, Fred Hutchinson Cancer Center, Seattle, WA
• Praveen Sethupathy, Cornell University College of Veterinary Medicine, Ithaca, NY
• Venu G. Pillarisetty, University of Washington, Seattle, WA

Document Type

Article

Publication Date

2-17-2026

Publication Title

Gastroenterology

Abstract

BACKGROUND & AIMS: Fibrolamellar carcinoma (FLC) is a rare liver cancer affecting young adults without underlying cirrhosis. Although almost all FLC patients share an immunogenic DNAJB1-PRKACA fusion oncogene, endogenous antitumor immunity and clinical response to immunotherapy are limited. We hypothesized that the lack of response to immunotherapy is mediated by both T-cell exclusion and intratumoral immunosuppression. METHODS: We used high-throughput single-nucleus RNA sequencing to explore the tumor immune microenvironment (TIME) of FLC. We then used multiplex immunohistochemistry, live imaging, single-cell sequencing, and spatial proteomics in a human tumor slice culture (TSC) system to dissect and experimentally modulate the FLC TIME. RESULTS: We identified significant dysregulation of stromal-immune signaling pathways within the FLC TIME relative to adjacent nontumor liver, notably including interactions between CXCL12 myofibroblasts and CXCR4 lymphocytes. CXCR4 inhibition was sufficient to mobilize stromal T cells into the carcinoma compartment, with the addition of PD-1 blockade independently activating T-cell antitumor effector function. Combination CXCR4 and PD-1 blockade resulted in a significant increase in tumor cell death relative to either treatment alone in a human TSC model. CONCLUSIONS: Our findings demonstrate that immune resistance in FLC is mediated by both local T-cell exclusion and exhaustion, with combination CXCR4 and PD-1 blockade acting cooperatively to overcome these independent mechanisms. These results highlight the versatility of the human TSC system to aid in the study of rare cancer types and provide important preclinical evidence for the rational design of combination immunotherapy in FLC, which currently lacks any effective systemic therapy.

First Page

787

Last Page

802

PubMed ID

41701126

Volume

170

Issue

4

Rights

© 2026 by the AGA Institute. Published by Elsevier Inc.

Recommended Citation

Carter, Jason A.; Dickerson, Lindsay K.; Stephanou, Andreas; Damle, Sheela R.; Goodsell, Kristin E.; Daniel, Sara K.; Sullivan, Kevin M.; Shui, Bo; Jiang, Xiuyun; Kenerson, Heidi L.; van den Bijgaart, Renske J.; Farghli, Alaa R.; Liu, Yongjun; Beirne, Emily; Labadie, Kevin P.; Cernak, Jack; Chauhan, Sardar Shahmir; Bello Pineda, Jose Mario; Long, Annalyssa N.; Elz, Anna E.; Newell, Evan W.; Kim, Teresa S.; Riehle, Kimberly J.; Yeung, Raymond S.; Akilesh, Shreeram; Crispe, Ian N.; Barry, Kevin C.; Sethupathy, Praveen; and Pillarisetty, Venu G., "Overcoming CXCR4-Mediated T-Cell Exclusion Potentiates Antitumor Cytotoxicity in Fibrolamellar Carcinoma" (2026). School of Medicine Faculty Publications. 4495.
https://digitalscholar.lsuhsc.edu/som_facpubs/4495
10.1053/j.gastro.2025.10.006