Myeloid-derived suppressor cell subset accumulation in renal cell carcinoma parenchyma is associated with intratumoral expression of IL1b, IL8, CXCL5, and Mip-1α

Yana G. Najjar, Patricia Rayman, Xuefei Jia, Paul G. Pavicic, Brian I. Rini, Charles Tannenbaum, Jennifer Ko, Samuel Haywood, Peter A Cohen, Thomas Hamilton, C. Marcela Diaz-Montero, James Finke

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37 Scopus citations

Abstract

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 immatureMDSC( I-MDSC) from the parenchyma and peripheral blood of 48 patients with RCC, isolated at nephrectomy. We analyzed levels of IL1β, IL8, CXCL5, Mip-1α, 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 IL1β blockade on MDSC. Results: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, 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 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. Conclusions: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, suggesting they may attract PMN-MDSC into the tumor. Peripheral PMNMDSC 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+ PMNMDSC are important in reducing activity of anti-PD1 antibody. Finally, anti-IL1β decreases MDSC and delayed tumor growth, suggesting a potential target for MDSC inhibition.

Original languageEnglish (US)
Pages (from-to)2346-2355
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number9
DOIs
StatePublished - May 1 2017

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Najjar, Y. G., Rayman, P., Jia, X., Pavicic, P. G., Rini, B. I., Tannenbaum, C., Ko, J., Haywood, S., Cohen, P. A., Hamilton, T., Diaz-Montero, C. M., & Finke, J. (2017). Myeloid-derived suppressor cell subset accumulation in renal cell carcinoma parenchyma is associated with intratumoral expression of IL1b, IL8, CXCL5, and Mip-1α. Clinical Cancer Research, 23(9), 2346-2355. https://doi.org/10.1158/1078-0432.CCR-15-1823