Abstract 403: Versican proteolysis in endometrial cancer

Abstract

Abstract Background: Endometrial cancer exhibits differential immunogenicity across molecular subtypes. Specifically, mismatch repair (MMR) deficiency in a subset of endometrial cancers increases mutational load, potentially leading to improved detection of tumor neoantigens within this context. The surrounding tumor microenvironment also plays a role in modulating the immune response to tumor neoantigens. The extracellular matrix protein versican (VCAN) has been characterized as an immunosuppressive molecule that is overexpressed in multiple cancer types, while its cleavage product, versikine (Vkine), has immunostimulatory properties. The objective of this study is to examine the relationship between VCAN proteolysis and CD8+ T cell tumor infiltration in endometrial cancer. Methods: An endometrial cancer tissue microarray (TMA) was developed containing tumor cores from 258 patients. TMA slides were stained via immunohistochemistry. VCAN and Vkine stains were scored on a scale of 0 to 3 based on intensity of stromal staining. Tumor-infiltrating lymphocytes (TILs) was quantified as the number of CD8+ T cells touching malignant epithelial cells 400X magnification. MMR proteins were scored as absent or present in each sample by pathology. Samples were classified into three groups based on strength of proteolysis: high proteolysis = VCAN 0 or 1 and Vkine 3, low proteolysis = VCAN 3 and Vkine 0 or 1. All other samples were put into the intermediate proteolysis group. Results: Proteolysis of VCAN correlates with increased CD8+ TILs in endometrial cancer. The CD8 mean in the proteolytic high group was 4-fold higher than that of the proteolytic low group (16.8 vs 3.6; Wilcoxon rank sum test, p=0.059; n=55 and n=8, respectively). High VCAN proteolysis, as well as mismatch repair deficiency, correlate with high CD8+ T cell infiltration of endometrial tumors; 78% of the MMR deficient samples, and 62% of the proteolysis high samples, were above the median CD8 count of 5.3. Furthermore, our results suggest that endometrial cancer recurrence is associated with increased VCAN expression in both type I endometrioid (estrogen-dependent) and type II non-endometrioid (estrogen-independent) cancers. Of the type I endometrioid cancers, 11% of those expressing VCAN recurred whereas 0% of non-VCAN expressing tumors recurred (n=92). Similarly, of the type II non-endometrioid cancers, 47% of VCAN expressing tumors recurred, whereas 20% of the non-VCAN expressing tumors recurred (n=80). Conclusions: VCAN and its proteolysis correlated with CD8+ TILs in endometrial cancer. These data indicate potential for VCAN as both a prognostic and an immune biomarker. Citation Format: Kristen Moriah Bischel, Philip Emmerich, Tonela Qyli, Stephanie McGregor, Mitchell Depke, Nathaniel Verhagen, Dustin Deming, Philip Emmerich, Nathaniel Verhagen, Tonela Qyli, Stephanie McGregor, Mitchell Depke. Versican proteolysis in endometrial cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 403.