HPB
Emilie A.K Warren, MD
Resident, Department of Surgery
Emory University, United States
Emilie A.K Warren, MD
Resident, Department of Surgery
Emory University, United States
Jacklyn N. Hammons, n/a
Senior Research Specialist
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
Jessica M. Keilson, MD
Resident, Department of Surgery
Emory University, United States
Guillermo O. Rangel Rivera, PhD
Graduate Student, MD PhD Candidate
Division of Surgical Oncology, Department of Surgery, Department of Microbiology and Immunology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
Megan M. Wyatt, MS
Research Lab Manager, Senior Scientist
Division of Surgical Oncology, Department of Surgery, Department of Microbiology and Immunology, Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
Caroline R. Goel, MD
Resident, Department of Surgery
Emory University, United States
Curtis J. Henry, PhD
Assistant Professor, Division of Hematology & Oncology, Department of Pediatrics
Emory University School of Medicine, United States
Sarah Kulkarni, n/a
Graduate student, Department of Biostatistics and Bioinformatics
Rollins School of Public Health, Emory University, United States
Yuan Liu, PhD, MS
Associate Professor, Department of Biostatistics and Bioinformatics
Rollins School of Public Health, Emory University, United States
Brian Robinson, MD, PhD
Assistant Professor, Department of Pathology and Laboratory Medicine
Emory University School of Medicine, United States
Alyssa M. Krasinskas, MD
Professor, Department of Pathology and Laboratory Medicine
Emory University School of Medicine, United States
Nilofer S. Azad, MD (she/her/hers)
Co-Director of Cancer Genetics and Epigenetics, Professor of Oncology
Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Mark Yarchoan, MD
Associate Professor
Johns Hopkins Hospital, United States
Shishir K. Maithel, MD, FACS
Professor, Department of Surgery
Winship Cancer Institute of Emory University
Atlanta, GA, United States
Chrystal M. Paulos, PhD
Associate Professor, Director of Translational Research for Cutaneous Malignancies, PI
Division of Surgical Oncology, Department of Surgery, Department of Microbiology and Immunology, Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
Gregory B. Lesinski, PhD, MPH
Professor, Co-Director Translational GI Malignancy Program
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
While results of the TOPAZ-1 trial led to inclusion of anti-PD-1 therapy with standard of care chemotherapy for unresectable biliary tract cancer (BTC), identification of novel therapeutic strategies remains a priority. Galectin-9 (Gal-9), a carbohydrate-binding protein, is expressed in BTC; known to be the ligand for Tim-3, it has various immunosuppressive effects. Defining the role of Gal-9 in the BTC microenvironment will inform how to leverage it as a therapeutic target.
Methods:
Tissue microarrays (TMAs) were constructed from tumors of 66 patients who underwent curative-intent resection of BTC from 2000- 2015 at our institution. These TMAs underwent IHC staining for CD4, CD8, Gal-9 & Tim-3 (Fig 1A). For each marker, the percentage of cells staining positive was quantified, and bias-adjusted log rank tests were used to identify a cut-off value of “low” vs “high” expression where survival difference was maximal. For in vivo experiments, the murine BTC cell line URCCA4.3 was injected subcutaneously into the flank of C57BL/6 mice, followed by 3 weeks of treatment with anti-Galectin-9 or anti-Tim-3 antibody alone or with anti-PD-1 antibody. Tumor-infiltrating lymphocytes (TILs) were analyzed by flow cytometry.
Results:
In patients with high Gal-9 expression, mOS was significantly improved compared to low Gal-9 expression (32.5 mos vs 17.6 mos, p = 0.02). However, when these patients were further stratified according to Tim-3, those with both high Gal-9 & high Tim-3 expression had significantly worse mOS than those with low Tim-3 (22.7 mos vs 113.9 mos, p = 0.03, Fig 1B), implying that Gal-9 and Tim-3 interaction wields significant impact on TIL function. There was no difference in mOS based on Tim-3 alone. When mice bearing BTC tumors were treated with anti-Gal-9 or anti-Tim-3 monotherapy, there was no significant change in tumor growth versus control, but when either was used in combination with PD-1 inhibition, there was a significant reduction in tumor burden at study endpoint. The TIL populations in mice treated with either dual therapy contained significantly more CD4+ T cells with stem-like properties (Tcf1+) and central memory phenotype, compared to the monotherapy groups (p< 0.05).
Conclusions:
This study provides unique insight into the role for targeting the Gal-9/Tim-3 pathway in BTC. Our clinical data highlights that co-expression of Gal-9 and Tim-3 is associated with significantly worse OS. Our in vivo pre-clinical work demonstrates that blockade of either Gal-9 or Tim-3 synergizes with anti-PD-1 therapy for superior anti-tumor efficacy.