RT Journal Article SR Electronic T1 High-dimensional analysis of the adenosine pathway in high-grade serous ovarian cancer JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e001965 DO 10.1136/jitc-2020-001965 VO 9 IS 3 A1 Yacine Bareche A1 Sandra Pommey A1 Mayra Carneiro A1 Laurence Buisseret A1 Isabelle Cousineau A1 Pamela Thebault A1 Pavel Chrobak A1 Laudine Communal A1 David Allard A1 Simon C Robson A1 Anne-Marie Mes-Masson A1 Diane Provencher A1 Rejean Lapointe A1 John Stagg YR 2021 UL http://jitc.bmj.com/content/9/3/e001965.abstract AB Background Hydrolysis of extracellular ATP to adenosine (eADO) is an important immune checkpoint in cancer immunology. We here investigated the impact of the eADO pathway in high-grade serous ovarian cancer (HGSC) using multiparametric platforms.Methods We performed a transcriptomic meta-analysis of eADO-producing CD39 and CD73, an eADO signaling gene signature, immune gene signatures and clinical outcomes in approximately 1200 patients with HGSC. Protein expression, localization and prognostic impact of CD39, CD73 and CD8 were then performed on approximately 1000 cases on tissue microarray, and tumor-infiltrating lymphocytes (TILs) were analyzed by flow cytometry and single-cell RNA sequencing on a subset of patients.Results Concomitant CD39 and CD73 gene expression, as well as high levels of an eADO gene signature, were associated with worse prognosis in patients with HGSC, notably in the immunoregulatory molecular subtype, characterized by an immune-active microenvironment. CD39 was further associated with primary chemorefractory and chemoresistant human HGSC and platinum-based chemotherapy of murine HGSC was significantly more effective in CD39-deficient mice. At protein level, CD39 and CD73 were predominantly expressed by cancer-associated fibroblasts, and CD39 was expressed on severely exhausted, clonally expanded and putative tissue-resident memory TILs.Conclusions Our study revealed the clinical, immunological, subtype-specific impacts of eADO signaling in HGSC, unveiled the chemoprotective effect of CD39 and supports the evaluation of eADO-targeting agents in patients with ovarian cancer.