Resistance to CTLA-4 checkpoint inhibition reversed through selective elimination of granulocytic myeloid cells

Paul E. Clavijo, Ellen C. Moore, Jianhong Chen, Ruth J. Davis, Jay Friedman, Young Kim, Carter Van Waes, Zhong Chen, Clint T. Allen

Research output: Contribution to journalArticle

Abstract

Purpose: Local immunosuppression remains a critical problem that limits clinically meaningful response to checkpoint inhibition in patients with head and neck cancer. Here, we assessed the impact of MDSC elimination on responses to CTLA-4 checkpoint inhibition. Experimental Design: Murine syngeneic carcinoma immune infiltrates were characterized by flow cytometry. Granulocytic MDSCs (gMDSCs) were depleted and T-lymphocyte antigen-specific responses were measured. Tumor-bearing mice were treated with MDSC depletion and CTLA-4 checkpoint blockade. Immune signatures within the human HNSCC datasets from The Cancer Genome Atlas (TCGA) were analyzed and differentially expressed genes from sorted human peripheral MDSCs were examined. Results: gMDSCs accumulated with tumor progression and correlated with depletion of effector immune cells. Selective depletion of gMDSC restored tumor and draining lymph node antigen-specific T-lymphocyte responses lost with tumor progression. A subset of T-cell inflamed tumors responded to CTLA-4 mAb alone, but the addition of gMDSC depletion induced CD8 T-lymphocyte-dependent rejection of established tumors in all treated mice that resulted in immunologic memory. MDSCs differentially expressed chemokine receptors. Analysis of the head and neck cancer TCGA cohort revealed high CTLA-4 and MDSC-related chemokine and an MDSC-rich gene expression profile with a T-cell inflamed phenotype in > 60% of patients. CXCR2 and CSF1R expression was validated on sorted peripheral blood MDSCs from HNSCC patients. Conclusions: MDSCs are a major contributor to local immunosuppression that limits responses to checkpoint inhibition in head and neck cancer. Limitation of MDSC recruitment or function represents a rational strategy to enhance responses to CTLA- 4-based checkpoint inhibition in these patients.

Original languageEnglish (US)
Pages (from-to)55804-55820
Number of pages17
JournalOncotarget
Volume8
Issue number34
DOIs
StatePublished - Jan 1 2017

Keywords

  • CTLA-4
  • MDSCs
  • Rejection
  • T-cell inflamed
  • TCGA

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Clavijo, P. E., Moore, E. C., Chen, J., Davis, R. J., Friedman, J., Kim, Y., Van Waes, C., Chen, Z., & Allen, C. T. (2017). Resistance to CTLA-4 checkpoint inhibition reversed through selective elimination of granulocytic myeloid cells. Oncotarget, 8(34), 55804-55820. https://doi.org/10.18632/oncotarget.18437