Abstract 4053: Misregulation of dicer miRNA processing correlates with antigen presentation and survival in colorectal cancer

Abstract

Abstract Background Tapasin is a crucial component of the major histocompatibility (MHC) class I antigen presentation pathway. The downregulation of the MHC I complex reduces the immunogenicity of tumors. We hypothesized that the expression of Tapasin may predict immune infiltration of colorectal cancer (CRC) by CD8+ cytotoxic T lymphocytes (CTLs) and overall survival. In vitro, the expression of Tapasin can be rescued by cytokine treatment, indicating that the misregulation is neither genetic nor structural and may occur on an epigenetic level. We therefore tested the possible involvement of the RNA silencing protein Dicer in the post-transcriptional regulation of Tapasin expression. Methods Resection specimens from 219 CRC patients with full clinicopathological information were included in this study. ngTMA (next generation tissue microarray) slides containing 8 punches from each case (tumor and normal tissue) were immunostained for MHC I pathway components (MHC I, beta-2-microglobuline, Calnexin, Calreticulin, Erp57 TAP1, TAP2 and Tapasin), Dicer and CD8. Marker expression was analyzed for immune activation, prediction of patient survival and TNM-staging. Results High Tapasin expression strongly correlated with lack of venous invasion (AUC: 0.682, p = 0.044, OR: 0.37; 95% CI: 0.2-0.69), lymphatic invasion (AUC: 0.727, p = 0.040, OR: 0.5; 95% CI: 0.3-0.8), absence of distant metastasis (AUC: 0.727, p = 0.040, OR: 0.35; 95% CI: 0.17-0.71) as well as a lack of infiltrative tumor border configuration (AUC: 0.621 p = 0.020, OR: 0.446; 95% CI: 0.23-0.87). Further, Tapasin expression correlated strongly with higher intra- and peritumoral CD8+ CTL invasion (AUC: 0.729, p<0.001, OR: 5.4; 95% CI: 2.6-11 and AUC: 0.650, p = 0.040, OR: 2.4 95% CI: 1.4-4.2, respectively). The prediction of CD8+ infiltration based on Tapasin was independent of the presence of other MHC I components. Furthermore, Tapasin expression was significantly associated with favorable overall survival (p = 0.004, OR: 0.6, 95% CI: 0.42-0.85). This effect was independent from the expression of the other MHC I components Calnexin, Calreticulin, Erp57, TAP1 and TAP2, but not independent of MHC I itself (p = 0.054) or Dicer expression (p = 0.068). Testing for a possible epigenetic regulation mechanism, we found that Dicer and Tapasin were positively correlated (r = 0.34, p<0.001). Conclusion Loss of Tapasin is an adverse prognostic factor in CRC. This may result from a reduced anti-tumoral CTL immune response driven by loss of Tapasin expression. Our results additionally suggest that Tapasin may be directly or indirectly regulated by RNA silencing and the Dicer protein. This may allow for further insight into the mechanism of epigenetic regulation of tumor immune evasion. Citation Format: Lena Sokol, Viktor H. Koelzer, Eva Karamitopoulou, Alessandro Lugli, Inti Zlobec. Misregulation of dicer miRNA processing correlates with antigen presentation and survival in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4053. doi:10.1158/1538-7445.AM2015-4053