Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells

Galina Gabriely; Duanduan Ma; Shafiuddin Siddiqui; Linqing Sun; Nathaniel P. Skillin; Hadi Abou-El-Hassan; Thais G. Moreira; Dustin Donnelly; Andre P. da Cunha; Mai Fujiwara; Lena R. Walton; Amee Patel; Rajesh Krishnan; Stuart S. Levine; Brian C. Healy; Rafael M. Rezende; Gopal Murugaiyan; Howard L. Weiner

iScience (Nov 2021)

Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells

Galina Gabriely,
Duanduan Ma,
Shafiuddin Siddiqui,
Linqing Sun,
Nathaniel P. Skillin,
Hadi Abou-El-Hassan,
Thais G. Moreira,
Dustin Donnelly,
Andre P. da Cunha,
Mai Fujiwara,
Lena R. Walton,
Amee Patel,
Rajesh Krishnan,
Stuart S. Levine,
Brian C. Healy,
Rafael M. Rezende,
Gopal Murugaiyan,
Howard L. Weiner

Affiliations

Galina Gabriely: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Jounce Therapeutics Inc, Cambridge, MA 02139, USA; Corresponding author
Duanduan Ma: MIT Biomicro Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
Shafiuddin Siddiqui: Flow Cytometry Core Facility, Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD 20892-4255, USA
Linqing Sun: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Northwestern University Interdepartmental Neuroscience Program, Northwestern University, Chicago, IL 60611, USA
Nathaniel P. Skillin: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Chemical and Biological Engineering, The BioFrontiers Institute, University of Colorado, Boulder, CO 80303, USA; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Hadi Abou-El-Hassan: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, University of New Mexico, Albuquerque, NM 87131, USA
Thais G. Moreira: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Dustin Donnelly: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Case Western Reserve University, Cleveland, OH 44106, USA
Andre P. da Cunha: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Jounce Therapeutics Inc, Cambridge, MA 02139, USA
Mai Fujiwara: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Lena R. Walton: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Novartis Institute of BioMedical Research, Cambridge, MA 02139, USA
Amee Patel: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Novartis Institute of BioMedical Research, Cambridge, MA 02139, USA
Rajesh Krishnan: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Stuart S. Levine: MIT Biomicro Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
Brian C. Healy: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Rafael M. Rezende: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Gopal Murugaiyan: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Howard L. Weiner: Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Corresponding author

Journal volume & issue: Vol. 24, no. 11
p. 103347

Abstract

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Summary: Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-β on their surface and LAPHi MCs that stimulate Foxp3+ Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-β inhibits the tolerogenic ability of LAPHi MCs. Furthermore, adoptive transfer of LAPHi MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAPHi MCs, slows cancer progression. Single-cell RNA-Seq analysis on tumor-derived immune cells revealed LAPHi dominated cell subsets with distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAPHi MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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