Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK-Cell Immunotherapy in Head and Neck Cancer Models

Abstract

Purpose: Natural killer (NK)-cell-based immunotherapy may overcome obstacles to effective T-cell-based immunotherapy such as the presence of genomic alterations in IFN response genes and antigen presentation machinery. All immunotherapy approaches may be abrogated by the presence of an immunosuppressive tumor microenvironment present in many solid tumor types, including head and neck squamous cell carcinoma (HNSCC). Here, we studied the role of myeloid-derived suppressor cells (MDSC) in suppressing NK-cell function in HNSCC.Experimental Design: The ability of peripheral and tumorinfiltrating MDSC from mice bearing murine oral cancer 2 (MOC2) non-T-cell-inflamed tumors and from patients with HNSCC to suppress NK-cell function was studied with real-time impedance and ELISpot assays. The therapeutic efficacy of SX-682, a smallmolecule inhibitor of CXCR1 and CXCR2, was assessed in combination with adoptively transferred NK cells.Results: Mice bearing MOC2 tumors pathologically accumulate peripheral CXCR2 þ neutrophilic-MDSC (PMN-MDSC) that traffic into tumors and suppress NK-cell function through TGFb and production of H 2 O 2 . Inhibition of MDSC trafficking with orally bioavailable SX-682 significantly abrogated tumor MDSC accumulation and enhanced the tumor infiltration, activation, and therapeutic efficacy of adoptively transferred murine NK cells. Patients with HNSCC harbor significant levels of circulating and tumor-infiltrating CXCR1/2 þ CD15 þ PMN-MDSC and CD14 þ monocytic-MDSC. Tumor MDSC exhibited greater immunosuppression than those in circulation. HNSCC tumor MDSC immunosuppression was mediated by multiple, independent, cell-specific mechanisms including TGFb and nitric oxide.Conclusions: The clinical study of CXCR1/2 inhibitors in combination with adoptively transferred NK cells is warranted.

The Emerging Role of Myeloid-Derived Suppressor Cells in the Glioma Immune Suppressive Microenvironment

“…Sinha et al proved that the COX-2 inhibitor, SC58236, delays primary tumor growth and reduces MDSC accumulation in spontaneously metastatic BALB/cderived 4T1 mammary carcinoma mouse (121).The chemokine receptor CXCR2 is a receptor of CXCL2 which was highly expressed in PMN-MDSC, andplay an important role in MDSCs recruitment (122). SX-682, a CXCR1/2 inhibitor, could block tumor MDSC recruitment and enhance T cell activation and anti-tumor immunity through various forms of immunotherapy (123,124).…”

Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy

“…Moreover, the production of IL-10 by MDSCs also affects the function of NK cells [1]. Treatment with the MDSC inhibitor SX-682 significantly improved the antitumor effect of NK cells [47]. MDSCs antagonize NK-cell Fc receptor-mediated functions, including cytokine production, signal transduction, and antibody-dependent cellular cytotoxicity, in a contact-independent manner via iNOS-dependent NO production [48].…”

Immunological Network in Head and Neck Squamous Cell Carcinoma—A Prognostic Tool Beyond HPV Status

“…Similarly, Chikamatsu et al (84) reported elevated levels and suppressive activities of MDSCs in the peripheral blood of HNSCC patients. In HPV-negative HNSCCs, tumor-derived MDSCs created a significant proportion of tumor-infiltrating immune cells and were capable of efficiently suppressing T cell (85) and natural killer (NK) cell functions (86). As all of these studies either did not specify the HPV status of the patients or included HNSCC patients with tumors localized outside the oropharynx, there is no report about the proportions and suppressive capacities of MDSCs in HPV-associated HNSCC to date.…”