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

doi:10.1016/j.isci.2021.103347

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

iScience. 2021 Oct 27;24(11):103347. doi: 10.1016/j.isci.2021.103347. eCollection 2021 Nov 19.

Authors

Galina Gabriely^{1

2}, Duanduan Ma³, Shafiuddin Siddiqui⁴, Linqing Sun^{1

5}, Nathaniel P Skillin^{1

6

7}, Hadi Abou-El-Hassan^{1

8}, Thais G Moreira¹, Dustin Donnelly^{1

9}, Andre P da Cunha^{1

2}, Mai Fujiwara¹, Lena R Walton^{1

10}, Amee Patel^{1

10}, Rajesh Krishnan¹, Stuart S Levine³, Brian C Healy¹, Rafael M Rezende¹, Gopal Murugaiyan¹, Howard L Weiner¹

Affiliations

¹ Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
² Jounce Therapeutics Inc, Cambridge, MA 02139, USA.
³ MIT Biomicro Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁴ Flow Cytometry Core Facility, Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD 20892-4255, USA.
⁵ Northwestern University Interdepartmental Neuroscience Program, Northwestern University, Chicago, IL 60611, USA.
⁶ Department of Chemical and Biological Engineering, The BioFrontiers Institute, University of Colorado, Boulder, CO 80303, USA.
⁷ Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁸ Department of Neurology, University of New Mexico, Albuquerque, NM 87131, USA.
⁹ Department of Neurosurgery, Case Western Reserve University, Cleveland, OH 44106, USA.
¹⁰ Novartis Institute of BioMedical Research, Cambridge, MA 02139, USA.

Abstract

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 LAP^Hi MCs that stimulate Foxp3⁺ Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-β inhibits the tolerogenic ability of LAP^Hi MCs. Furthermore, adoptive transfer of LAP^Hi MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAP^Hi MCs, slows cancer progression. Single-cell RNA-Seq analysis on tumor-derived immune cells revealed LAP^Hi 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 LAP^Hi MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer.

Keywords: Cancer; Immunology.

Abstract

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