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
AIMS 1 & 2 4
AIM 3 14
STRENGTHS AND LIMITATIONS: AIMS 1 & 2 24
STRENGTHS AND LIMITATIONS: AIM 3 24
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
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
About this Master's Thesis
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