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
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.
