3127 Background: Immune checkpoint inhibitors (ICIs) represent a major advance for treating solid tumors. However, only a minority of patients (pts) benefit from these therapies and markers that predict response have been elusive. Versican (VCAN) is an immunosuppressive proteoglycan in the tumor microenvironment (TME), which releases an immunostimulatory N-terminal fragment versikine (Vkine) when cleaved by ADAMTS proteases. We have demonstrated in colorectal cancers (CRC) that a low VCAN/high Vkine (VCAN proteolytic predominant [VPP]) phenotype correlates with increased tumor-infiltrating CD8+ T lymphocytes (TILs). Here we examine the accumulation of VCAN as a marker of immune exclusion and its proteolysis as a marker of an immune-permissive TME. Methods: Immunohistochemistry for VCAN, Vkine and CD8+ was performed on samples from 1662 pts across breast (BC), CRC, endometrial cancer, pancreatic adenocarcinoma (PDAC), esophageal cancers and neuroendocrine tumors (NETs), across stages of disease (I-IV) and with diverse prior treatments. Stromal intensities of VCAN and Vkine staining quantified in collaboration with blinded surgical pathologists using a 0-3+ scale. 0/1+ were considered “low” for both VCAN and Vkine, whereas 2/3+ were considered “high”. The number of CD8+ TILs were counted using 400x magnification, the equivalent of a high power field (hpf). Results: Across the entire cohort VCAN phenotypes were diverse (VCAN high/Vkine low, 21%; VCAN high/Vkine high, 23%; VCAN low/Vkine low, 29%; VCAN low/Vkine high (VPP), 27%). Consistent with VCAN accumulation as a marker of T cell exclusion, VCAN low cancers had increased TILs compared to VCAN high (4.8 vs 18.3 TILs/hpf, p < 0.001). Low VCAN was identified in 85% esophageal, 79% NET (including small cell lung cancer [SCLC]) 72% endometrial, 47% MSI-H CRCs, 28% triple-negative BC and only 22% MSS CRC, 18% PDAC, 17% ER+ BCs. The VPP subgroup had the highest TILs per hpf across tumors. VPP was identified in 47% of esophageal, 45% endometrial, 41% NETs (including SCLC), 24% MSI-H CRCs, and only 9% MSS CRC, 7% ER+ BCs, 3% triple-negative BCs, and 0% of PDAC (n = 131 PDAC pts). Conclusions: VCAN accumulation correlates with T lymphocyte exclusion, while VCAN proteolysis predicts an immune permissive phenotype. VCAN accumulation and proteolysis are now incorporated into ICI clinical trials as a potential marker of response. Future studies will clarify the role of these biomarkers in predicting benefits of immuno-oncology treatment strategies.
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.
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