High-dimensional analysis of the adenosine pathway in high-grade serous ovarian cancer

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.

[1]  S. Robson,et al.  Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis. , 2020, Journal of hepatology.

[2]  A. Khoruts,et al.  Sensing of ATP via the Purinergic Receptor P2RX7 Promotes CD8+ Trm Cell Generation by Enhancing Their Sensitivity to the Cytokine TGF-β. , 2020, Immunity.

[3]  L. Buisseret,et al.  The adenosine pathway in immuno-oncology , 2020, Nature Reviews Clinical Oncology.

[4]  R. Knobler,et al.  Recent advances in understanding and managing cutaneous T-cell lymphomas , 2020, F1000Research.

[5]  P. Park,et al.  Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer , 2020, Nature Communications.

[6]  E. Vadillo,et al.  Myo1e modulates the recruitment of activated B cells to inguinal lymph nodes , 2020, Journal of Cell Science.

[7]  Manish R. Patel,et al.  Adenosine Signaling Is Prognostic for Cancer Outcome and Has Predictive Utility for Immunotherapeutic Response , 2020, Clinical Cancer Research.

[8]  R. Drapkin,et al.  Mouse Ovarian Cancer Models Recapitulate the Human Tumor Microenvironment and Patient Response to Treatment , 2020, Cell reports.

[9]  J. Madore,et al.  Targeting CD39 in cancer reveals an extracellular ATP and inflammasome driven tumor immunity. , 2019, Cancer discovery.

[10]  P. LoRusso,et al.  Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of patients with advanced solid malignancies , 2019, Journal of Immunotherapy for Cancer.

[11]  G. Coukos,et al.  Immunotherapy in Ovarian Cancer: Are We There Yet? , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  E. Swisher,et al.  Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma. , 2019, JAMA oncology.

[13]  D. Provencher,et al.  Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[14]  P. Bose,et al.  TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure , 2018, Nature Communications.

[15]  Christoph Hafemeister,et al.  Comprehensive integration of single cell data , 2018, bioRxiv.

[16]  Gregory M. Chen,et al.  Consensus on Molecular Subtypes of High-Grade Serous Ovarian Carcinoma , 2018, Clinical Cancer Research.

[17]  D. Gerhard,et al.  Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T-Cell Receptors in High-Risk MYCN-Not-Amplified Human Neuroblastoma , 2018, Clinical Cancer Research.

[18]  M. Fehlings,et al.  Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates , 2018, Nature.

[19]  C. Le Page,et al.  Characteristics and outcome of the COEUR Canadian validation cohort for ovarian cancer biomarkers , 2018, BMC Cancer.

[20]  U. Cavallaro,et al.  CD73 Regulates Stemness and Epithelial-Mesenchymal Transition in Ovarian Cancer-Initiating Cells , 2018, Stem cell reports.

[21]  A. Whittemore,et al.  Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer , 2017, JAMA oncology.

[22]  Boxi Kang,et al.  Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing , 2017, Cell.

[23]  Deborah S. Barkauskas,et al.  Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses. , 2016, Cancer cell.

[24]  J. Wischhusen,et al.  Adenosine-generating ovarian cancer cells attract myeloid cells which differentiate into adenosine-generating tumor associated macrophages – a self-amplifying, CD39- and CD73-dependent mechanism for tumor immune escape , 2016, Journal of Immunotherapy for Cancer.

[25]  Benjamin Haibe-Kains,et al.  MetaGxData: Clinically Annotated Breast, Ovarian and Pancreatic Cancer Datasets and their Use in Generating a Multi-Cancer Gene Signature , 2016, Scientific Reports.

[26]  Joel S. Parker,et al.  Genefu: an R/Bioconductor package for computation of gene expression-based signatures in breast cancer , 2016, Bioinform..

[27]  E. Nevedomskaya,et al.  A Systems Oncology Approach Identifies NT5E as a Key Metabolic Regulator in Tumor Cells and Modulator of Platinum Sensitivity. , 2016, Journal of proteome research.

[28]  R. Broaddus,et al.  Loss of CD73-mediated actin polymerization promotes endometrial tumor progression. , 2015, The Journal of clinical investigation.

[29]  P. Linsley,et al.  MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data , 2015, Genome Biology.

[30]  Deena M. A. Gendoo,et al.  CD73 is associated with poor prognosis in high-grade serous ovarian cancer. , 2015, Cancer research.

[31]  Joshy George,et al.  Whole–genome characterization of chemoresistant ovarian cancer , 2015, Nature.

[32]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[33]  Todd H. Stokes,et al.  Removing Batch Effects From Histopathological Images for Enhanced Cancer Diagnosis , 2014, IEEE Journal of Biomedical and Health Informatics.

[34]  M. Smyth,et al.  Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1 and Anti-CTLA-4 mAbs , 2013, Clinical Cancer Research.

[35]  S. Loi,et al.  CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer , 2013, Proceedings of the National Academy of Sciences.

[36]  Jung-Hye Choi,et al.  Overexpression of CD73 in epithelial ovarian carcinoma is associated with better prognosis, lower stage, better differentiation and lower regulatory T cell infiltration , 2012, Journal of gynecologic oncology.

[37]  G. Coukos,et al.  Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. , 2012, Gynecologic oncology.

[38]  T. Curiel,et al.  CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. , 2011, The Journal of clinical investigation.

[39]  Bin Zhang.  CD73: a novel target for cancer immunotherapy. , 2010, Cancer research.

[40]  for the Statistics Subcommittee of the NCI—EORTC Worki Diagnostics.  REporting recommendations for tumor MARKer prognostic studies (REMARK) , 2005, Nature Clinical Practice Oncology.

[41]  George Coukos,et al.  Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. , 2003, The New England journal of medicine.

[42]  Editeur,et al.  The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27 , 2017 .

[43]  Deena M. A. Gendoo,et al.  CD 73 Is Associated with Poor Prognosis in High-Grade Serous Ovarian Cancer , 2015 .