Abstract A16: Natural killer cell therapy efficacy is enhanced through inhibition of myeloid-derived suppressor cell trafficking

Abstract

Abstract Immunotherapies designed to activate or replace T-cell effector immunity, such as immune checkpoint blockade or adoptive transfer of T cells, are limited by the ability of subpopulations of tumor cells to escape T-cell immunity. This can occur through immunologic selection of tumor cells that present weak T-cell antigens or harbor genomic or epigenetic alterations that alter antigen processing or presentation or responses to interferon. Immunotherapy designed to activate or replace NK cell immunity may overcome these limitations through antigen and MHC class I-independent tumor cell recognition and killing. However, similar to suppression of T-cell function, local immunosuppression within the tumor microenvironment may limit the function of NK cells. We hypothesized that immature, immunosuppressive myeloid cells (myeloid derived suppressor cells, or MDSCs) may limit optimal function of NK cells and that NK cell control of tumors can be enhanced through abrogation of MDSC trafficking and tumor infiltration. To model new NK cell therapy products that are available for clinical investigation, we studied how MDSCs alter the ability of culturable murine NK (KIL) cell line to kill oral cancer cells. We used an oral cancer model, MOC2, that has few genomic alterations and forms highly aggressive, non-T cell-inflamed tumors in wild-type C57BL/6 mice. CXCR2+ neutrophilic-MDSCs (PMN-MDSCs) sorted from MOC2 tumors significantly suppressed the ability of KIL to kill MOC2 tumor cells in vitro as assessed by real-time impedance analysis. NK suppression mediated by PMN-MDSC appeared to be mediated by both cell surface TGFβ and arginase. In vivo, we aimed to block chemotaxis and MOC2 tumor infiltration of CXCR2+ PMN-MDSC with the use of SX-682, a clinical-stage small-molecule inhibitor of CXCR1/2. After validating that SX-682 blocks tumor PMN-MDSC trafficking into tumors, we treated mice bearing established MOC2 tumors with SX-682 and adoptive transfer of KIL, alone or in combination. While SX-682 alone produced no tumor growth inhibition (TGI) and KIL adoptive transfer alone produced modest TGI, the combination resulted in significant TGI and prolonged survival of mice. Immune correlative analysis revealed increased tumor infiltration of adoptively transferred KIL with inhibition of PMN-MDSC tumor infiltration. These data suggest that the efficacy of NK cell therapies can be enhanced with PMN-MDSC inhibition and support the clinical investigation of chemokine receptor inhibitors such as SX-682 in combination with NK cell therapy products. Citation Format: Sarah Greene, Yvette Robbins, Paul E. Clavijo, Dean Maeda, John Zebala, Jeffrey Schlom, Claudia Palena, Clint Allen. Natural killer cell therapy efficacy is enhanced through inhibition of myeloid-derived suppressor cell trafficking [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A16.