684 IMPACT OF REGIONAL Foxp3 EXPRESSION WITHIN THE TUMOR MICROENVIRONMENT ON TUMOR BIOLOGY AND MORTALITY IN HEPATITIS B-ASSOCIATED HEPATOCELLULAR CARCINOMA

Abstract

Background and Aims: Foxp3-expressing regulatory T cells impede effective immune surveillance against cancer and inhibit anti-tumor immune responses, thereby influencing the biological behavior of many, but not all tumors. This study aims to determine the microenvironment-specific influence of Foxp3 expression on tumor biology of hepatitis B-associated hepatocellular carcinoma (HBVHCC). Methods: This prospective study includes 90 HBV-HCC surgical resection patients enrolled between 2008–2012 at the Mount Sinai Medical Center in New York. Foxp3 mRNA in four regions of the resection specimens (center of the tumor, periphery of the tumor, non-neoplastic liver bordering tumor, non-neoplastic liver distant from tumor) was quantitated for each case using real-time PCR. Resection specimens were assessed by a single dedicated liver pathologist to evaluate tumor characteristics as well as liver fibrosis using the Ishak method. Results: Foxp3 mRNA was detectable in all four regions of all the samples. While no differences were observed in median Foxp3 expression between tumor and non-neoplastic liver, Foxp3 expression in center of the tumor showed the greatest variance and skewed most towards the highest values (variance: 1603, 371, 66 and 110; and skewness: 6.8, 4.0, 3.4, 2.3, in center of the tumor, periphery of the tumor, non-neoplastic liver bordering tumor, nonneoplastic liver distant from tumor, respectively). This high variance in the tumor was due to the high variance in the highest quintile of Foxp3 expression, and was not observed in tumors that were associated with less fibrotic liver (Ishak stage 1–4), or in tumors that were well-differentiated. High Foxp3 expression in the tumor (highest quintile) was associated with mortality (6/17 (35%) vs. 5/64 (8%), p = 0.009). Likewise, mortality was associated with high Foxp3 expression (13.1 vs. 2.7, p = 0.015) and high variance (9325 vs. 524) in center of the tumor, but not in the other three compartments. Conclusions: A small population of HBV-HCC patients (20%) had high Foxp3 expression within the tumor microenvironment that is highly variable and associated with mortality following surgical resection. Therefore, HCC predominated by a Foxp3dependent immune-suppressive environment is associated with poor prognosis following surgical resection.