Myeloid derived suppressor cell subset accumulation in renal cell carcinoma parenchyma is associated with intratumoral expression of IL-1β, IL-8, CXCL5 and Mip-1α

Abstract

Purpose

Little is known about the association between MDSC subsets and various chemokines in patients with RCC, or the factors that draw MDSC into tumor parenchyma.

Experimental Design

We analyzed PMN-MDSC, M-MDSC and I-MDSC from the parenchyma and peripheral blood of 48 RCC patients, isolated at nephrectomy. We analyzed levels of IL-1β, IL-8, CXCL5, Mip-1α, MCP-1 and Rantes. Furthermore, we performed experiments in a Renca murine model to assess therapeutic synergy between CXCL2 and anti-PD1, and to elucidate the impact of IL-1β blockade on MDSC.

Results

Parenchymal PMN-MDSC have a positive correlation with IL-1β, IL-8, CXCL-5 and Mip-1α, and I-MDSC correlate with IL-8 and CXCL-5. Furthermore, peripheral PMN-MDSC correlate with tumor grade. Given that PMN-MDSC express CXCR2, and parenchymal PMN-MDSC correlated with IL-8 and CXCL5, we assessed the response of CXCR2 blockade with or without anti-PD1. Combination therapy reduced tumor weight and enhanced CD4+ and CD8+ T cell infiltration. In addition, anti-IL1β decreased PMN-MDSC and M-MDSC in the periphery, PMN-MDSC in the tumor, and peripheral CXCL5 and KC. Anti-IL1β also delayed tumor growth.

Conslusion

Parenchymal PMN-MDSC have a positive correlation with IL-1 β, IL-8, CXCL-5 and Mip-1α, 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-PD-1 antibody. Lastly, anti-IL1β decreases MDSC and delayed tumor growth, suggesting a potential target for MDSC inhibition.