Distinct Cell Adhesion Signature Defines Glioblastoma Myeloid-Derived Suppressor Cell Subsets

Author:

Bayik Defne12ORCID,Bartels Cynthia F.3ORCID,Lovrenert Katreya3ORCID,Watson Dionysios C.124ORCID,Zhang Duo5ORCID,Kay Kristen1ORCID,Lee Juyeun1ORCID,Lauko Adam167ORCID,Johnson Sadie1ORCID,Lo Alice1ORCID,Silver Daniel J.12ORCID,McGraw Mary8ORCID,Grabowski Matthew8ORCID,Mohammadi Alireza M.8ORCID,Veglia Filippo9ORCID,Fan Yi5ORCID,Vogelbaum Michael A.10ORCID,Scacheri Peter23ORCID,Lathia Justin D.128ORCID

Affiliation:

1. 1Lerner Research Institute, Cleveland Clinic, Ohio.

2. 2Case Comprehensive Cancer Center, Cleveland, Ohio.

3. 3Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio.

4. 4University Hospitals Cleveland Medical Center, Cleveland, Ohio.

5. 5Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.

6. 6Department of Pathology, Case Western Reserve University, Cleveland, Ohio.

7. 7Case Western Reserve University, Medical Science Training Program, Cleveland, Ohio.

8. 8Rose Ella Burkhardt Brain Tumor Center, Cleveland Clinic, Ohio.

9. 9Department of Immunology, Moffitt Cancer Center, Tampa, Florida.

10. 10Department of Neuro-oncology, Moffitt Cancer Center, Tampa, Florida.

Abstract

Abstract In multiple types of cancer, an increased frequency in myeloid-derived suppressor cells (MDSC) is associated with worse outcomes and poor therapeutic response. In the glioblastoma (GBM) microenvironment, monocytic (m) MDSCs represent the predominant subset. However, the molecular basis of mMDSC enrichment in the tumor microenvironment compared with granulocytic (g) MDSCs has yet to be determined. Here we performed the first broad epigenetic profiling of MDSC subsets to define underlying cell-intrinsic differences in behavior and found that enhanced gene accessibility of cell adhesion programs in mMDSCs is linked to their tumor-accelerating ability in GBM models upon adoptive transfer. Mouse and human mMDSCs expressed higher levels of integrin β1 and dipeptidyl peptidase-4 (DPP-4) compared with gMDSCs as part of an enhanced cell adhesion signature. Integrin β1 blockade abrogated the tumor-promoting phenotype of mMDSCs and altered the immune profile in the tumor microenvironment, whereas treatment with a DPP-4 inhibitor extended survival in preclinical GBM models. Targeting DPP-4 in mMDSCs reduced pERK signaling and their migration towards tumor cells. These findings uncover a fundamental difference in the molecular basis of MDSC subsets and suggest that integrin β1 and DPP-4 represent putative immunotherapy targets to attenuate myeloid cell-driven immune suppression in GBM. Significance: Epigenetic profiling uncovers cell adhesion programming as a regulator of the tumor-promoting functions of monocytic myeloid-derived suppressor cells in glioblastoma, identifying therapeutic targets that modulate the immune response and suppress tumor growth.

Funder

National Institute of Neurological Disorders and Stroke

National Cancer Institute

National Heart, Lung, and Blood Institute

American Heart Association

Case Western Reserve University

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Reference54 articles.

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