Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment.

Autor:	Egan H; Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland., Treacy O; Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland., Lynch K; Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland., Leonard NA; Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland., O'Malley G; Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland., Reidy E; Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland., O'Neill A; Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland., Corry SM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., De Veirman K; Laboratory for Haematology and Immunology (HEIM), Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium., Vanderkerken K; Laboratory for Haematology and Immunology (HEIM), Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium., Egan LJ; Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland., Ritter T; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland., Hogan AM; Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Department of Colorectal Surgery, Galway University Hospital, Galway, Ireland., Redmond K; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Peng L; Palleon Pharmaceuticals, Waltham, MA 02451, USA., Che J; Palleon Pharmaceuticals, Waltham, MA 02451, USA., Gatlin W; Palleon Pharmaceuticals, Waltham, MA 02451, USA., Jayaraman P; Palleon Pharmaceuticals, Waltham, MA 02451, USA., Sheehan M; Division of Anatomical Pathology, Galway University Hospital, Galway, Ireland., Canney A; Division of Anatomical Pathology, Galway University Hospital, Galway, Ireland., Hynes SO; Division of Anatomical Pathology, Galway University Hospital, Galway, Ireland; Discipline of Pathology, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland., Kerr EM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Dunne PD; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK; Cancer Research UK Beatson Institute, Glasgow, UK., O'Dwyer ME; Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Blood Cancer Network of Ireland (BCNI), Galway, Ireland; Department of Hematology, Galway University Hospital, Galway, Ireland., Ryan AE; Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland. Electronic address: aideen.ryan@universityofgalway.ie.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 May 30; Vol. 42 (5), pp. 112475. Date of Electronic Publication: 2023 May 10.
DOI:	10.1016/j.celrep.2023.112475
Abstrakt:	Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions. The role of sialylation in shaping MSC/CAF immunosuppression in the TME is not well characterized. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid, and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory CD8 + PD1 + and CD8 + Siglec-7 + /Siglec-9 + T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as shown by infiltration of CD25 and granzyme B-expressing CD8 + T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME. Competing Interests: Declaration of interests L.P., W.G., J.C., and P.J. are employees and shareholders of Palleon Pharmaceuticals. M.E.O'D. is a founder of ONK Therapeutics and a member of its Board of Directors and is co-inventor on two related patents (US20210186999A1 and US2017032727899A1). K.L., T.R., and A.E.R. are co-inventors on patent US20210186999A1. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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