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
Itsaso Montalbán del Barrio,Cornelia Penski,Cornelia Penski,Laura Schlahsa,Roland Stein,J Diessner,Achim Wöckel,Johannes Dietl,Manfred B. Lutz,Michel Mittelbronn,Michel Mittelbronn,Jörg Wischhusen,Sebastian Häusler +12 more
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TLDR
Adenosine generated by OvCA cells likely contributes to the recruitment of TAMs which further amplify adenosine-dependent immunosuppression via additional ectonucleotidase activity, which could improve immune responses in ovarian cancer.Abstract:
Ovarian cancer (OvCA) tissues show abundant expression of the ectonucleotidases CD39 and CD73 which generate immunomodulatory adenosine, thereby inhibiting cytotoxic lymphocytes. Little, however, is known about the effect of adenosine on myeloid cells. Considering that tumor associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) constitute up to 20 % of OvCA tissue, we investigated the effect of adenosine on myeloid cells and explored a possible contribution of myeloid cells to adenosine generation in vitro and ex vivo. Monocytes were used as human blood-derived myeloid cells. After co-incubation with SK-OV-3 or OAW-42 OvCA cells, monocyte migration was determined in transwell assays. For conversion into M2-polarized “TAM-like” macrophages, monocytes were co-incubated with OAW-42 cells. Ex vivo TAMs were obtained from OvCA ascites. Macrophage phenotypes were investigated by intracellular staining for IL-10 and IL-12. CD39 and CD73 expression were assessed by FACS analysis both on in vitro-induced TAM-like macrophages and on ascites-derived ex situ-TAMs. Myeloid cells in solid tumor tissue were analyzed by immunohistochemistry. Generation of biologically active adenosine by TAM-like macrophages was measured in luciferase-based reporter assays. Functional effects of adenosine were investigated in proliferation-experiments with CD4+ T cells and specific inhibitors. When CD39 or CD73 activity on OvCA cells were blocked, the migration of monocytes towards OvCA cells was significantly decreased. In vivo, myeloid cells in solid ovarian cancer tissue were found to express CD39 whereas CD73 was mainly detected on stromal fibroblasts. Ex situ-TAMs and in vitro differentiated TAM-like cells, however, upregulated the expression of CD39 and CD73 compared to monocytes or M1 macrophages. Expression of ectonucleotidases also translated into increased levels of biologically active adenosine. Accordingly, co-incubation with these TAMs suppressed CD4+ T cell proliferation which could be rescued via blockade of CD39 or CD73. Adenosine generated by OvCA cells likely contributes to the recruitment of TAMs which further amplify adenosine-dependent immunosuppression via additional ectonucleotidase activity. In solid ovarian cancer tissue, TAMs express CD39 while CD73 is found on stromal fibroblasts. Accordingly, small molecule inhibitors of CD39 or CD73 could improve immune responses in ovarian cancer.read more
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Journal ArticleDOI
Macrophages and Metabolism in the Tumor Microenvironment
TL;DR: The metabolic circuitries whereby TAMs condition the TME to support tumor growth and how such pathways can be therapeutically targeted are discussed.
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The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets.
TL;DR: Insight into potential clinical application of adenosinergic and other purinergic‐targeting therapies and forecast how these might develop in combination with other anti‐cancer modalities are provided.
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Consensus guidelines for the definition, detection and interpretation of immunogenic cell death
Lorenzo Galluzzi,Ilio Vitale,Sarah Warren,Sandy Adjemian,Patrizia Agostinis,Aitziber Burque Martinez,Timothy A. Chan,George Coukos,Sandra Demaria,Eric Deutsch,Dobrin Draganov,Richard L. Edelson,Silvia C. Formenti,Jitka Fucikova,Lucia Gabriele,Udo S. Gaipl,Sofia R. Gameiro,Abhishek D. Garg,Encouse B. Golden,Jian Han,Kevin J. Harrington,Kevin J. Harrington,Akseli Hemminki,James W. Hodge,Dewan Md Sakib Hossain,Timothy M Illidge,Michael Karin,Howard L. Kaufman,Oliver Kepp,Guido Kroemer,Juan José Lasarte,Sherene Loi,Michael T. Lotze,Gwenola Manic,Taha Merghoub,Taha Merghoub,Alan Melcher,Karen L. Mossman,Felipe Prosper,Øystein Rekdal,Maria Rescigno,Chiara Riganti,Antonella Sistigu,Mark J. Smyth,Radek Spisek,John Stagg,Bryan E. Strauss,Daolin Tang,Kazuki Tatsuno,Stefaan Van Gool,Peter Vandenabeele,Takahiro Yamazaki,Dmitriy Zamarin,Dmitriy Zamarin,Laurence Zitvogel,Alessandra Cesano,Francesco M. Marincola +56 more
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TL;DR: The complex interplay ofadenosine and adenosine receptors in the development of primary tumours and metastases is described and the merits of targeting one or more components that compose the adenosinergic pathway are discussed.
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Extracellular ATP and P2 purinergic signalling in the tumour microenvironment
TL;DR: How extracellular ATP and P2 purinergic signalling can shape the tumour microenvironment to both promote and restrain tumour progression is described and the opportunities to harness nucleotide receptor signalling as an anticancer strategy are outlined.
References
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Journal ArticleDOI
Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression
Silvia Deaglio,Karen M. Dwyer,Wenda Gao,David J. Friedman,Anny Usheva,Anna Erat,Jiang-Fan Chen,Keiichii Enjyoji,Joel Linden,Mohamed Oukka,Vijay K. Kuchroo,Terry B. Strom,Simon C. Robson +12 more
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