CXCR2 Blockade Improves Response to Hypo-fractionated Radiation Treatment in a Murine Head and Neck Squamous Cell Carcinoma (HNSCC) Model.

Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is known for high levels of disease recurrence and resistance to conventional fractionated radiation therapy. In an analysis of primary patient HPV-negative HNSCC biopsies from our institutional tumor bank, we observed circulating and tumor-resident monocytic myeloid-derived suppressor cells (M-MDSCs) were enriched in patient samples from recurrent HPV-negative HNSCCs relative to treatment-naïve samples. To determine if radiation exposure alters myeloid chemotaxis to the tumor site, we measured myeloid chemotactic factor transcript expression in eight cancer-associated fibroblast (CAF) and EpCAM-expressing patient-derived malignant cell lines. In malignant cell lines, radiation exposure increased transcriptional expression of CCL5 and C-X-C ligand receptor 2 (CXCR2) ligands CXCL2 and CXCL8 (IL-8). Based on this finding, we evaluated whether an antagonist of CXCR2 (SB225002) in combination with radiation blocked murine MDSC chemotaxis in vivo and in vitro. Antagonism of CXCR2 signaling with SB225002, in combination with radiation, suppressed tumor growth, improved survival, and reduced intra-tumoral macrophages in a murine MOC1 model. Additionally, radiation-induced MDSC chemotaxis was inhibited by SB225002 in a transwell assay. Together, these data suggest CXCR2 inhibition in combination with radiation has therapeutic potential for treatment of HPV-negative HNSCC.