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

Abstract

PurposeLocal 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 DesignMurine 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.ResultsgMDSCs 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.ConclusionsMDSCs 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.

Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells

“…For some experiments, spleen and tumors were harvested from mice and processed into single cell suspensions for flow analysis. Only fresh tissues processed as described(21) were analyzed. Following FcR block, primary conjugated antibodies were applied for 45 minutes.…”

Glioblastoma myeloid-derived suppressor cell subsets express differential macrophage migration inhibitory factor receptor profiles that can be targeted to reduce immune suppression

“…Here we found that the receptor CD74 may play a greater role in GBM MDSC biology because the subset of MDSCs primarily found in the tumor microenvironment were M-MDSCs, which primarily express CD74 as a MIF receptor. This is in contrast to metastatic breast cancer models that show G-MDSCs infiltrating tumors and driving metastasis 57,58 ; where in those cases we would hypothesize that CXCR2 or another MIF receptor may play a more vital role.…”

Therapeutic prospects of targeting myeloid‐derived suppressor cells and immune checkpoints in cancer

“…Inhibition of CXCR2 + G‐MDSC trafficking to the TME by CXCR2 targeting with anti‐CXCR2 monoclonal antibody in murine rhabdomyosarcoma model improved anti‐PD‐1 treatment . Moreover, expansion of G‐MDSC correlated with reduced effector immune cell infiltration in head and neck cancer tumor model, while selective depletion of G‐MDSC by administration of anti‐Ly6G antibody significantly improved response to anti‐CTLA‐4 treatment and induced CD8 + T‐cell killing of tumor cells . These results suggest that expansion of MDSC in the TME impair checkpoint blockade in cancer.…”