B. A. Krasnick1, S. M. Husain2, Y. Bi1, P. V. Dickson2,3, J. Deneve2,3, D. Shibata2,3, R. Fields1, W. G. Hawkins1, E. S. Glazer2,3 1Washington University,Surgery,St. Louis, MO, USA 2University Of Tennessee Health Science Center,Surgery,Memphis, TN, USA 3University Of Tennessee West Cancer Center,Surgery,Memphis, TN, USA
Introduction: Pancreatic ductal adenocarcinoma (PDAC) carries the highest case fatality rate of any cancer and will likely become the second leading cause of death by 2020. TGF-ß has a paradoxical relationship with survival in PDAC patients where it is a tumor suppressor in early stage PDAC and a tumor promotor in late stage PDAC. While TGF-ß is known to drive inflammation in the tumor microenvironment (TME), the role of interleukins in the pancreatic TME is not well understood. We hypothesized that IL23, a pro-inflammatory interleukin associated with suppression of cytotoxic T cells, is associated with survival in PDAC.
Methods: 24 long-term survivors (>30 months) and 24 short-term survivors (<12 months) with resected PDAC were identified. Tumor sections were taken from formalin fixed, paraffin embedded blocks and protein expression of IL-23 and TGF-ß were independently investigated with immunohistochemistry utilizing quantitative analysis with CellProfiler image analysis software. Immunohistochemistry expression of IL23 or TGF-ß was determined to be high (highest quartile), low (lowest quartile), or median (within the interquartile range) based on 5 representative images of each tumor section. Comparisons with clinical outcomes were investigated with Student’s t-test, ANOVA, or multivariate regression.
Results: There was no significant difference in the average age (66 ± 12 years), gender (44% male), or clinical stage between the two groups. Patients with low TGF-ß protein expression were more likely to be in the short-term survival group (OR=2.2, P=0.018). Tumors from short-term survivors were significantly more likely to have low IL23 expression (OR=0.48, P=0.019). In long-term survivors, neither TGF-ß nor IL-23 protein expression was associated with survival (P>0.05). There was no difference in IL23 expression in low or median TGF-ß expressing tumors (P>0.5), however, in high TGF-ß expressing tumors, long-term survivors were associated with 20% higher IL23 protein expression (P=0.008). Multivariate analysis demonstrated that long-term survival was linearly associated with increasing IL23 expression (OR=3, P=0.001) but not TGF-ß expression (P=0.07). Overall, we also found a statistical association between IL23 expression and TGF-ß expression (P<0.001) and that long-term survival was associated with a higher ratio of IL23 / TGF-ß expression (P=0.04).
Conclusion: We found that IL23 tumor expression is associated with survival after PDAC resection in short-term survivors and statistically related to TGF-ß expression for all patients. While other groups have shown that TGF-ß is associated with survival in PDAC, we demonstrated that IL23 may be a critical component to understanding the relationship between TGF-ß expression and survival in patients with survival less than 12 months.