Using the T-cell-inflamed mouse oral cancer 1 (MOC1) model, Clavijo et al. found that depletion of granulocytic myeloid-derived suppressor cells (gMDSCs) rescued the lytic function of intra-tumoral effector T lymphocytes and NK cells and sensitized MOC1 tumors to CTLA-4 checkpoint blockade, leading to complete rejection and immunologic memory. The CXCR2 chemokine was linked to recruiting gMDSCs to the tumor.
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.
Author Info: (1) Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA. (2) Tum
Author Info: (1) Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA. (2) Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA. (3) Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA. (4) Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA. (5) Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA. (6) Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA. (7) Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA. (8) Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA. (9) Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA. Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA.
