Galectin-9 Expression and its Role in Biliary Tract Cancers Open Access

Abstract

Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies often refractory to chemotherapeutic or targeted therapies, carrying a poor prognosis and high mortality. Identifying prognostic biomarkers and effective therapeutic targets for this disease therefore remains a high priority. TIM-3 is a negative regulatory immune checkpoint receptor known to induce immune tolerance and inhibit T-cell antitumor immunity. Its ligand, galectin-9 (gal-9), plays a paradoxical role in tumorigenesis in numerous disease states. However, the role of gal-9 in the setting of BTCs is not completely understood.

Membrane-bound and soluble gal-9 expression were examined in a unique panel of six human BTC cells. Membrane-bound gal-9 is differentially expressed across all BTC cell lines in vitro; however, only some cell lines also secrete gal-9. There does not seem to be a correlation between membrane-bound and soluble gal-9 expression levels among cell lines that express both forms. BTC cell viability is unaffected by antibody-mediated gal-9 neutralization.

Baseline plasma was isolated from 74 patients with metastatic BTC (NCI10139) and soluble gal-9 expression was measured. Patients were dichotomized by low and high soluble gal-9 expression, a cut point that was identified using cox proportional hazards modeling for differences in overall survival. Age, sex, and line of treatment were similar between groups (all p>0.6). A greater proportion of patients with intrahepatic cholangiocarcinoma (65%, n=26) and extrahepatic cholangiocarcinoma (87%, n=13) had low soluble gal-9 expression, whereas patients with gallbladder cancer were nearly equally distributed between groups (p=0.05). No clinicopathologic variables were associated with an increased odds of high soluble gal-9 expression.

On Kaplan-Meier analysis, high soluble gal-9 expression was associated with worse overall survival (p=0.013). When controlling for site of disease, high sGal-9 expression remained significantly associated with a higher hazard rate of death compared to low sGal-9 expression (HR 1.782, 95% CI 1.067-2.977, p=0.027). Thus, soluble galectin-9 expression may be related to a more aggressive disease state.

Additional work is needed to better inform the mechanistic role of the galectin-9 on disease progression and how best to leverage the galectin-9/TIM-3 pathway as a therapeutic target in the management of biliary tract cancers.

Table of Contents

INTRODUCTION 1

AIMS 1 & 2 4

METHODS 5

RESULTS 8

DISCUSSION 10

CONCLUSIONS 13

AIM 3 14

METHODS 15

RESULTS 17

DISCUSSION 20

CONCLUSIONS 23

STRENGTHS AND LIMITATIONS: AIMS 1 & 2 24

STRENGTHS AND LIMITATIONS: AIM 3 24

CONCLUSIONS 26

FIGURES 27

Figure 1. Human biliary tract cancer cell line site of origin diagram and methods schema 27

Figure 2. Human biliary tract cancer membrane-bound and soluble gal-9 expression in vitro 28

Figure 3. Human biliary tract cancer cell viability following antibody-mediated gal-9 neutralization 29

Figure 4. Site-specific soluble gal-9 expression and Kaplan-Meier analysis for overall survival 30

TABLES 31

Table 1. Demographic and clinicopathologic factors for all patients 31

Table 2. Exploratory analysis using cox proportional hazards modeling to identify an optimal cut-point for soluble galectin-9 (sGal-9) expression and a difference in overall survival 32

Table 3. Demographic and clinicopathologic factors for all patients, stratified by low soluble galectin-9 (sGal-9) and high sGal-9 33

Table 4. Univariate binary logistic regression for the association between clinicopathologic variables and high soluble galectin-9 (sGal-9) expression 34

Table 5. Univariate and multivariable cox proportional hazards regression models for overall survival 35

Supplementary Table 1. Subset analysis of all patients, stratified by treatment allocation 36

REFERENCES 37

ACKNOWLEDGMENTS 40

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Oncology Health Sciences, Immunology
Keyword	Galectin-9 Biliary tract cancers
Committee Chair / Thesis Advisor	Amita Manatunga, PhD, Emory University
Committee Members	Gregory B. Lesinski, PhD MPH, Emory University Brian S. Robinson, MD PhD, Emory University Shishir K. Maithel, MD, Emory University

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