Abstract 2798: CD73 suppresses anti-cancer immunity and promotes glycolysis, resulting in poor prognosis in pancreatic ductal adenocarcinoma

Abstract

Abstract CD73 is a cell surface enzyme involved in adenosine metabolism by converting extracellular adenosine-triphosphate to adenosine together with CD39. Accumulated extracellular adenosine is known to play pro-cancer role, by promoting angiogenesis, leading immune suppression, accelerating tumor growth, and metastasis in some types of malignancies. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, we investigated clinical significance and possible roles of CD73 in PDAC by bioinformatical using publicly available cohorts (TCGA, E-MTAB, ICGC) and experimental approaches using murine pancreatic and human pancreatic cancer cells. First, we found that PDAC patients with high CD73 expression showed worse prognosis in all three PDAC patient cohorts (overall survival (OS) in TCGA; P=0.002, disease-free survival (DFS) in TCGA; P=0.012, E-MTAB; P<0.001, ICGC; P=0.002). In addition, infiltrated immune cell analysis by xCell algorism revealed lower CD8-positive T cell infiltration in CD73 high expressing PDACs in two cohorts (TCGA; P=0.009, E-MTAB; P<0.001). To confirm the role of CD73 in immune suppression in PDAC, we established Panc02 carcinomatosis mouse model using CD73 overexpressed cells. We found that the mice bearing CD73 overexpressed tumors showed shorter survival in immune competent mice, however, there was no survival difference in immune deficient mice. Consistent with patient samples, infiltrated CD8-positive T cells were significantly lower in CD73 overexpressed tumors compared to control tumors in immune competent mice (P=0.041). There were very weak to no correlations of CD73 expression with CD39 or adenosine receptors, including ADORA1, ADORA2A, ADORA2B, ADORA3 in all three cohorts. On the other hand, we found that CD73 high expressing PDACs were positively correlated with glycolytic pathway in all three patient cohorts (TCGA; P=0.018, E-MTAB; P=0.004, ICGC; P=0.039). Consistently, CD73 knockdown PANC1 cells showed lower baseline glycolysis (P=0.023) and glycolytic capacity (P=0.014) compared to control cells by Seahorse assay. CD73 expression was positively correlated with cancer stem cell markers, CD44 and cMET in all three cohorts. CD73 was also positively correlated with hypoxia-associated genes in patient samples, which is one of cancer stem cell features. In conclusion, we found that PDAC patients with CD73 high expressing tumors have worse prognosis. As a possible mechanism, we observed immune suppressive role of CD73 in PDAC similar to other cancers. By further elucidating CD73 transcriptional regulation in hypoxic condition and how glycolysis is connected to CD73 upregulation, we will demonstrate by experimental approaches. Citation Format: Eriko Katsuta, Mariko Asaoka, Tao Dai, Li Yan, Subhamoy Dasgupta, Kazuaki Takabe. CD73 suppresses anti-cancer immunity and promotes glycolysis, resulting in poor prognosis in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2798.