title: Myeloid-Derived Suppressor Cell Subset Accumulation in Renal Cell Carcinoma Parenchyma Is Associated with Intratumoral Expression of IL1β, IL8, CXCL5, and Mip-1α.
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 immature MDSC (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 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-IL1β decreases MDSC and delayed tumor growth, suggesting a potential target for MDSC inhibition.Clin Cancer Res; 23(9); 2346-55. ©2016 AACR.
authors: Department of Hematology-Oncology, University of Pittsburgh Cancer Institite, Pittsburgh, Pennsylvania.
authors: Yana G
authors: YG
authors: Najjar
authors: Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio.
authors: Patricia
authors: P
authors: Rayman
authors: Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, Ohio.
authors: Xuefei
authors: X
authors: Jia
authors: Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio.
authors: Paul G
authors: PG
authors: Pavicic
authors: Cleveland Clinic Foundation, Taussig Cancer Center, Cleveland, Ohio.
authors: Brian I
authors: BI
authors: Rini
authors: Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio.
authors: Charles
authors: C
authors: Tannenbaum
authors: Pathology Institute, Cleveland Clinic, Cleveland, Ohio.
authors: Jennifer
authors: J
authors: Ko
authors: Department of Urology, Cleveland Clinic Foundation, Cleveland, Ohio.
authors: Samuel
authors: S
authors: Haywood
authors: Division of Hematology-Oncology, Mayo Clinic, Scottsdale, Arizona.
authors: Peter
authors: P
authors: Cohen
authors: Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio.
authors: Thomas
authors: T
authors: Hamilton
authors: Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio. diazc2@ccf.org.
authors: C Marcela
authors: CM
authors: Diaz-Montero
authors: Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio.
authors: James
authors: J
authors: Finke
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D054405:Chemokine CCL3 / Q000235:genetics*; D054365:Chemokine CXCL5 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics*; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000072356:Parenchymal Tissue / Q000378:metabolism / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000235:genetics; D047368:Tumor Burden / Q000235:genetics
chemical_list: D054405:Chemokine CCL3; D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; D053583:Interleukin-1beta; D016209:Interleukin-8; D061026:Programmed Cell Death 1 Receptor; D023063:Receptors, Interleukin-8B