Sandrine Medves

Arbed (Luxembourg)

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Guy Berchem

Centre Hospitalier de Luxembourg

Jean‐Baptiste Demoulin

de Duve Institute

Bassam Janji

Luxembourg Institute of Health

Elodie Viry

Luxembourg Institute of Health

Joanna Bagińska

Dana-Farber Cancer Institute

François P. Duhoux

Cliniques Universitaires Saint-Luc

Etienne Moussay

Luxembourg Institute of Health

Federica Toffalini

de Duve Institute

Salem Chouaı̈b

Inserm

Hélène A. Poirel

Sciensano (Belgium)

Cooperative Institutions

Luxembourg Institute of Health

Inserm

UCLouvain

Laboratoire National de Santé

Cliniques Universitaires Saint-Luc

University of Luxembourg

Centre National de la Recherche Scientifique

de Duve Institute

Centre Hospitalier de Luxembourg

Universidad Pablo de Olavide

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Elsevier eBooks (2016)

José A. Sánchez Alcázar Sebastiano Andò Tsolère Arakelian Guy Berchem Daniela Bonofiglio

10.1016/b978-0-12-802937-4.00021-1

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Jak2-independent hematopoietic cell proliferation and stat5 activation by the kank1-pdgfrb fusion associated with thrombocythemia

Experimental Hematology (2011)

Jean‐Baptiste Demoulin Sandrine Medves Carmen Patricia Montano Almendras Laura A. Noël Roxana Irina Albu

PDGFRB

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Autophagic degradation of GZMB/granzyme B

Autophagy (2013)

Elodie Viry Joanna Bagińska Guy Berchem Muhammad Zaeem Noman Sandrine Medves

The crucial issue for defining successful natural killer (NK)-based anticancer therapy is the ability of tumor cells to activate resistance mechanisms leading to escape from NK-mediated killing. It is now well established that such mechanisms are likely evolved under hypoxia in the tumor microenvironment. Here, we show that hypoxia-induced autophagy impairs breast cancer cell susceptibility to NK-mediated lysis and that this impairment is reverted by targeting autophagy. We provide evidence that activation of autophagy in hypoxic cells is involved in selective degradation of the pro-apoptotic NK-derived serine protease GZMB/granzyme B, thereby blocking NK-mediated target cell apoptosis. Our in vivo data validate the concept that targeting autophagy in cancer cells promotes tumor regression by facilitating their elimination by NK cells. This study provides a cutting-edge advance in our understanding of how hypoxia-induced autophagy impairs NK-mediated lysis and might pave the way for formulating more effective NK-based antitumor therapy by combining autophagy inhibitors.

Granzyme

10.4161/auto.26924

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Citations (79)

An integrative simulation model linking major biochemical reactions of actin-polymerization to structural properties of actin filaments

Biophysical Chemistry (2008)

Aliaksandr Halavatyi Petr V. Nazarov Sandrine Medves Marleen Van Troys Christophe Ampè

10.1016/j.bpc.2008.11.006

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Citations (12)

Characterization of a KANK1-PDGFRB fusion in an imatinib-responsive myeloproliferative neoplasm with severe thrombocythemia

Haematologica-the Hematology Journal (2010)

Sandrine Medves François P. Duhoux Augustin Ferrant Federica Toffalini Geneviève Ameye

PDGFRB

Myeloproliferative neoplasm

Myeloproliferative Disorders

Neoplasm

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Abstract 156: Autophagic degradation of granzyme B impairs NK-mediated killing of hypoxic tumor cells

Cancer Research (2014)

Joanna Bagińska Elodie Viry Guy Berchem Aurélie Poli Muhammad Zaeem Noman

Abstract Natural killer (NK) cells are effectors of the innate immune system, able to kill cancer cells through the release of the cytotoxic protease granzyme B. NK-based therapies have recently emerged as promising anticancer strategies. However, it is well established that hypoxic tumor microenvironment interferes with the antitumor function of immune cells and constitutes a major obstacle for defining cancer immunotherapies. Recent studies demonstrated that autophagy regulates the innate immune response by mechanisms which are not fully understood. In this study, we showed that hypoxia decreases breast cancer cell susceptibility to NK-mediated lysis by a mechanism involving the activation of autophagy in tumor cells. Targeting autophagy was sufficient to restore NK-mediated tumor cell killing. We showed that the resistance of hypoxic tumor cells was neither related to a defect in their recognition by NK cells, nor to a defect in the cytolytic function of NK cells toward hypoxic cells. We provided evidence that autophagy activation degrades NK-derived granzyme B in lysosomes of hypoxic cells making them less sensitive to NK-mediated killing. Genetic and pharmacological inhibition of autophagy restored granzyme B levels and reverted the resistance of hypoxic cells in vitro. Our results highlight autophagy as a critical factor in modulating NK-mediated anti-tumor immune response. We have validated this concept in vivo by showing that targeting autophagy significantly improved NK-mediated tumor shrinking in breast and melanoma models. This study provides a cutting-edge advance in our understanding of how hypoxia-induced autophagy impairs NK-mediated lysis and paves the way for formulating more effective NK-based antitumor therapy by combining autophagy inhibitors. Citation Format: Joanna Baginska, Elodie Viry, Guy Berchem, Aurélie Poli, Muhammad Zaeem Noman, Kris van Moer, Sandrine Medves, Takouhie Mgrditchian, Jacques Zimmer, Anais Oudin, Simone P. Niclou, R. Chris Bleackley, Salem Chouaib, Bassam Janji. Autophagic degradation of granzyme B impairs NK-mediated killing of hypoxic tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 156. doi:10.1158/1538-7445.AM2014-156

Granzyme

NK-92

10.1158/1538-7445.am2014-156

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The Critical Role of the Tumor Microenvironment in Shaping Natural Killer Cell-Mediated Anti-Tumor Immunity

Frontiers in Immunology (2013)

Joanna Bagińska Elodie Viry Jérôme Paggetti Sandrine Medves Guy Berchem

Considerable evidence has been gathered over the last 10 years showing that the tumor microenvironment (TME) is not simply a passive recipient of immune cells, but an active participant in the establishment of immunosuppressive conditions. It is now well documented that hypoxia, within the TME, affects the functions of immune effectors including natural killer (NK) cells by multiple overlapping mechanisms. Indeed, each cell in the TME, irrespective of its transformation status, has the capacity to adapt to the hostile TME and produce immune modulatory signals or mediators affecting the function of immune cells either directly or through the stimulation of other cells present in the tumor site. This observation has led to intense research efforts focused mainly on tumor-derived factors. Notably, it has become increasingly clear that tumor cells secrete a number of environmental factors such as cytokines, growth factors, exosomes, and microRNAs impacting the immune cell response. Moreover, tumor cells in hostile microenvironments may activate their own intrinsic resistance mechanisms, such as autophagy, to escape the effective immune response. Such adaptive mechanisms may also include the ability of tumor cells to modify their metabolism and release several metabolites to impair the function of immune cells. In this review, we summarize the different mechanisms involved in the TME that affect the anti-tumor immune function of NK cells.

10.3389/fimmu.2013.00490

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Citations (175)

Novel variant form of t(11;22)(q23;q13)/MLL-EP300 fusion transcript in the evolution of an acute myeloid leukemia with myelodysplasia-related changes

Leukemia Research (2010)

François P. Duhoux Sigrid De Wilde Geneviève Ameye Khadija Bahloula Sandrine Medves

10.1016/j.leukres.2010.09.024

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Citations (7)

Fusion of PDGFRB with a candidate tumor suppressor gene in an imatinib-responsive myeloid neoplasm with severe thrombocythemia

François P. Duhoux Sandrine Medves Augustin Ferrant Federica Toffalini Geneviève Ameye

PDGFRB