Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy

• Published in: JCI insight 2019-04, Vol.4 (7)
• Main Authors: Sun, Lillian, Clavijo, Paul E, Robbins, Yvette, Patel, Priya, Friedman, Jay, Greene, Sarah, Das, Rita, Silvin, Chris, Van Waes, Carter, Horn, Lucas A, Schlom, Jeffrey, Palena, Claudia, Maeda, Dean, Zebala, John, Allen, Clint T
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Carcinoma - immunology; Carcinoma - pathology; Carcinoma - therapy; Cell Line, Tumor - transplantation; Cell Movement - drug effects; Cell Movement - immunology; Combined Modality Therapy - methods; Disease Models, Animal; Humans; Immune Tolerance - drug effects; Immunotherapy, Adoptive - methods; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Lymphocytes, Tumor-Infiltrating - immunology; Mice; Mouth Neoplasms - immunology; Mouth Neoplasms - pathology; Mouth Neoplasms - therapy; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - metabolism; Neutrophils - immunology; Neutrophils - metabolism; Receptors, Interleukin-8A - antagonists & inhibitors; Receptors, Interleukin-8A - immunology; Receptors, Interleukin-8A - metabolism; Receptors, Interleukin-8B - antagonists & inhibitors; Receptors, Interleukin-8B - immunology; Receptors, Interleukin-8B - metabolism; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - transplantation; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.126853

Recruitment of myeloid-derived suppressor cells (MDSCs) into tumors induces local immunosuppression in carcinomas. Here, we assessed whether SX-682, an orally bioavailable small-molecule inhibitor of CXCR1 and CXCR2, could block tumor MDSC recruitment and enhance T cell activation and antitumor immunity following multiple forms of immunotherapy. CXCR2+ neutrophilic MDSCs (PMN-MDSCs) were the most abundant myeloid cell subset within oral and lung syngeneic carcinomas. PMN-MDSCs demonstrated greater suppression of tumor-infiltrating lymphocyte killing of targets compared with macrophages. SX-682 significantly inhibited trafficking of PMN-MDSCs without altering CXCR2 ligand expression. Trafficking of CXCR1+ macrophages was unaltered, possibly due to coexpression of CSF1R. Reduced PMN-MDSC tumor infiltration correlated with enhanced accumulation of endogenous or adoptively transferred T cells. Accordingly, tumor growth inhibition or the rate of established tumor rejection following programed death-axis (PD-axis) immune checkpoint blockade or adoptive cell transfer of engineered T cells was enhanced in combination with SX-682. Despite CXCR1/2 expression on tumor cells, SX-682 appeared to have little direct antitumor effect on these carcinoma models. These data suggest that tumor-infiltrating CXCR2+ PMN-MDSCs may prevent optimal responses following both PD-axis immune checkpoint blockade and adoptive T cell transfer therapy. Abrogation of PMN-MDSC trafficking with SX-682 enhances T cell-based immunotherapeutic efficacy and may be of benefit to patients with MDSC-infiltrated cancers.