Abstract 1687: Checkpoint inhibitor signatures across endometrial cancer histologies
Authors: Amanda Ramos, Sarah Fortin, Victoria Melchert, David Jenkins, Whitfield Growdon, Darrell Borger
Journal: Cancer Research (2018)

Abstract Background: Therapies targeting immune checkpoints have revolutionized cancer treatment. However, biomarkers that effectively stratify patients to these therapies are required. Endometrial carcinomas consist of several histologies and a subset harbor hypermutation/microsatellite instability (MSI) that has been associated with response to PD-1 inhibition. The purpose of this study was to investigate the immune checkpoint landscape across endometrial cancer subtypes and ascertain whether more complex signatures indicate directions for combination immune therapies in efforts to improve patient response. Methods: With IRB approval, 60 diagnostic endometrial tumor samples were obtained from 2013-2017 consisting of MSI low grade endometrioid (n=11), microsatellite stable (MSS) low grade endometrioid (n=11), high grade endometrioid (n=16), carcinosarcoma (n=11), and uterine serous carcinoma (n=11) histologies. Immune RNA expression signatures were evaluated using a Luminex platform that evaluated 142 gene targets, including inflammation mediators, immune checkpoints, immune cell type and immune cell polarity markers. Expression of RNA for genes encoding CTLA-4, PD-1, PD-L1, LAG-3, and TIM-3 were quantified and correlated with clinical outcomes utilizing parametric and non-parametric testing. These signatures will be further investigated with multispectral imaging, including proximity analysis. Results: Cohort characteristics included 32 patients with stage 1A, 9 patients with stage 1B, 6 with stage II, 8 with stage III and 5 with stage IV disease. The median age at diagnosis was 66 years. RNA expression for CTLA-4, PD-1, PD-L1, LAG-3, and TIM-3 were compared across the various endometrial carcinoma histologies. While there were no significant differences noted between carcinosarcoma and serous carcinoma, levels of TIM-3 and CTLA-4 expression were significantly elevated in endometrioid carcinoma (P&amp;lt;0.01, P&amp;lt;0.001 respectively). When evaluating expression within endometrioid subtypes, high grade tumors were independently associated with elevated checkpoint expression (LAG-3 (P=0.04), PD-L1 (P=0.04), and CTLA-4 (P=0.04)), as was the presence of MSI (TIM-3 (P=0.02), PD-L1 (P=0.01), and CTLA-4 (P=0.014). When both grade and MSI were factored together, PD-1 was significantly elevated in MSI high grade versus MSI low grade cancers (P=0.04). RNA expression levels for PD-L1 and PD-L2 were also significantly elevated in endometrioid cancers. Preliminary analysis suggests that recurrent tumors demonstrate altered levels of immune checkpoint signatures compared to those that do not. Conclusion: A complex landscape of regulatory immune receptors was found across endometrial cancer histologies, with particular relevance in endometrioid carcinomas that was grade and MSI-dependent. These data suggest directions for combined immune blockade therapy in this cancer type. Citation Format: Amanda Ramos, Sarah Fortin, Victoria Melchert, David Jenkins, Whitfield Growdon, Darrell Borger. Checkpoint inhibitor signatures across endometrial cancer histologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1687.