Tumor sialylation impedes T cell mediated anti-tumor responses while promoting tumor associated-regulatory T cells

// Maurizio Perdicchio 1, 4 , Lenneke A. M. Cornelissen 1 , Ingeborg Streng-Ouwehand 1 , Steef Engels 1 , Marleen I. Verstege 1 , Louis Boon 2 , Dirk Geerts 3 , Yvette van Kooyk 1, * , Wendy W. J. Unger 1, 5, * 1 Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands 2 EPIRUS Biopharmaceuticals, Leiden, The Netherlands 3 Department of Pediatric Oncology/Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands 4 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 5 Department of Pediatrics, Division of Infectious Diseases, ErasmusMC-Sophia Children's Hospital, Rotterdam, The Netherlands * These authors have contributed equally and share senior authorship Correspondence to: Yvette van Kooyk, e-mail: y.vankooyk@vumc.nl Keywords: sialic acid, tumor, immune regulation, regulatory T cells, natural killer cells Received: August 03, 2015      Accepted: November 25, 2015      Published: January 05, 2016 ABSTRACT The increased presence of sialylated glycans on the tumor surface has been linked to poor prognosis, yet the effects on tumor-specific T cell immunity are hardly studied. We here show that hypersialylation of B16 melanoma substantially influences tumor growth by preventing the formation of effector T cells and facilitating the presence of high regulatory T cell (Treg) frequencies. Knock-down of the sialic acid transporter created “sialic acid low” tumors, that grew slower in-vivo than hypersialylated tumors, altered the Treg/Teffector balance, favoring immunological tumor control. The enhanced effector T cell response in developing “sialic acid low” tumors was preceded by and dependent on an increased influx and activity of Natural Killer (NK) cells. Thus, tumor hypersialylation orchestrates immune escape at the level of NK and Teff/Treg balance within the tumor microenvironment, herewith dampening tumor-specific T cell control. Reducing sialylation provides a therapeutic option to render tumors permissive to immune attack.