Abstract IA022: Harnessing the unique biology of CD73 for improving endometrial cancer outcomes

Abstract

Abstract Uncovering mechanisms that contribute to the unique pathobiology of endometrial cancer has the potential to reveal opportunities for improving outcomes. CD73, a cell surface 5’nucleotidase that generates adenosine, has emerged as an attractive therapeutic target; inhibiting CD73 therapeutically restores antitumor immune responses. While anti-CD73 agents appear promising for several cancer types, the biology of CD73 in endometrial cancer is proving to be complex and distinct from other solid tumors. Here, we present two unpublished studies of novel roles for CD73 that diverge from current paradigms. Critically, we show how the unique biology of CD73 in endometrial cancer can be leveraged to improve patient outcomes. We previously reported that although CD73 is upregulated in many tumors, supporting tumorigenesis, CD73 is downregulated in aggressive (grade 3 endometrioid and serous) endometrial carcinomas and its loss is associated with poor outcomes. First, we show through comprehensive immunohistochemistry (n=119) and TCGA computational analyses of microsatellite stable grade 2 endometrioid endometrial carcinomas with intact mismatch repair that loss of CD73, as opposed to its upregulation (as seen in other tumors), reprograms endometrial cancer cells to develop immunosuppressive features. CD73 cancer cell downregulation results in proinflammatory cytokine/chemokine (e.g., CXCL10, CXCL9, CCL8, IL11, IL32) upregulation. Consequently, to counterbalance the inflammatory environment, cancer cells upregulate immunosuppressive genes (e.g., PD-L1). Second, we reveal that CD73 critically restrains the oncogenic transcriptional activity of mutant β-catenin. Mutations in exon 3 of CTNNB1 (the gene that encodes β-catenin) occur in ~26% of low grade endometrioid endometrial carcinomas. CD73 sequesters exon 3 mutant β-catenin (β-cateninEX3) to the membrane, dampening its oncogenic transcriptional activity. A clinical challenge with β-cateninEX3 mutant endometrioid tumors is that half of these patients recur and will have poor outcomes. We show low CD73 expression in endometrioid tumors independently predicts disease recurrence and therefore CD73 may serve as a predictive biomarker where none currently exists. Moreover, we have identified that CD73 differentially controls different patient-specific β-cateninEX3 mutants. Understanding the unique mechanisms of CD73 signaling in endometrial cancer will reveal opportunities for precision medicine strategies. Our studies highlight the continued need and opportunities that exist from focused efforts elucidating the molecular mechanisms driving endometrial cancer. Citation Format: Jessica L. Bowser, Hannah N. Lee, Rebecca H. Hirsch, Xingyuan Zhang, Russell R. Broaddus, Katherine C. Kurnit, Suzanne M. Crumley, Sunthoshini Premsankar, Emily M. Rabjohns, Lilly F. Chiou, Cyrus Vaziri. Harnessing the unique biology of CD73 for improving endometrial cancer outcomes [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA022.