Myeloid-Derived Suppressor Cell Subset Accumulation in Renal Cell Carcinoma Parenchyma Is Associated with Intratumoral Expression of IL1β, IL8, CXCL5, and Mip-1α

Purpose: Little is known about the association between myeloid-derived suppressor cell (MDSC) subsets and various chemokines in patients with renal cell carcinoma (RCC) or the factors that draw MDSC into tumor parenchyma. Experimental Design: We analyzed polymorphonuclear MDSC (PMN-MDSC), monocytic MDSC (M-MDSC), and immature-MDSC(I-MDSC) from the parenchyma and peripheral blood of 48 patients with RCC, isolated at nephrectomy. We analyzed levels of IL1 beta, IL8, CXCL5, Mip-1 alpha, MCP-1, and Rantes. Furthermore, we performed experiments in a Renca murine model to assess therapeutic synergy between CXCR2 and anti-PD1 and to elucidate the impact of IL1b blockade on MDSC. Results: Parenchymal PMN-MDSC have a positive correlation with IL1b, IL8, CXCL5, and Mip-1a, and I-MDSC correlate with IL8 and CXCL5. Furthermore, peripheral PMN-MDSC correlate with tumor grade. Given that PMN-MDSC express CXCR2 and parenchymal PMN-MDSC correlated with IL8 and CXCL5, we assessed the response of CXCR2 blockade with or without antiPD1. Combination therapy reduced tumor weight and enhanced CD4(+) and CD8(+) T-cell infiltration. In addition, anti-IL1 beta decreased PMN-MDSC and M-MDSC in the periphery, PMN-MDSC in the tumor, and peripheral CXCL5 and KC. Anti-IL1 beta also delayed tumor growth. Conclusions: Parenchymal PMN-MDSC have a positive correlation with IL1 beta, IL8, CXCL5, and Mip-1a, suggesting they may attract PMN-MDSC into the tumor. Peripheral PMN-MDSC correlate with tumor grade, suggesting prognostic significance. Anti-CXCR2 and anti-PD1 synergized to reduce tumor weight and enhanced CD4(+) and CD8(+) T-cell infiltration in a Renca murine model, suggesting that CXCR2(+) PMN-MDSC are important in reducing activity of anti-PD1 antibody. Finally, anti-IL1b decreases MDSC and delayed tumor growth, suggesting a potential target for MDSC inhibition. (C) 2016 AACR.