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Myeloid-Derived Suppressor Cell Subset Accumulation in Renal Cell

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Myeloid-Derived Suppressor Cell Subset Accumulation in Renal Cell Published OnlineFirst October 31, 2016; DOI: 10.1158/1078-0432.CCR-15-1823 Biology of Human Tumors Clinical Cancer Research Myeloid-Derived Suppressor Cell Subset Accumulation in Renal Cell Carcinoma Parenchyma Is Associated with Intratumoral Expression of IL1b, IL8, CXCL5, and Mip-1a Yana G. Najjar1, Patricia Rayman2, Xuefei Jia3, Paul G. Pavicic Jr2, Brian I. Rini4, Charles Tannenbaum2, Jennifer Ko5, Samuel Haywood6, Peter Cohen7, Thomas Hamilton2, C. Marcela Diaz-Montero2, and James Finke2 Abstract Purpose: Little is known about the association between mye- assessed the response of CXCR2 blockade with or without anti- loid-derived suppressor cell (MDSC) subsets and various chemo- PD1. Combination therapy reduced tumor weight and enhanced þ þ kines in patients with renal cell carcinoma (RCC) or the factors CD4 and CD8 T-cell infiltration. In addition, anti-IL1b decreas- that draw MDSC into tumor parenchyma. ed PMN-MDSC and M-MDSC in the periphery, PMN-MDSC in Experimental Design: We analyzed polymorphonuclear the tumor, and peripheral CXCL5 and KC. Anti-IL1b also delayed MDSC (PMN-MDSC), monocytic MDSC (M-MDSC), and imma- tumor growth. ture MDSC (I-MDSC) from the parenchyma and peripheral blood Conclusions: Parenchymal PMN-MDSC have a positive cor- of 48 patients with RCC, isolated at nephrectomy. We analyzed relation with IL1b,IL8,CXCL5,andMip-1a,suggesting levels of IL1b, IL8, CXCL5, Mip-1a, MCP-1, and Rantes. Further- they may attract PMN-MDSC into the tumor. Peripheral more, we performed experiments in a Renca murine model PMN-MDSC correlate with tumor grade, suggesting prognostic to assess therapeutic synergy between CXCR2 and anti-PD1 and significance. Anti-CXCR2 and anti-PD1 synergized to reduce þ þ to elucidate the impact of IL1b blockade on MDSC. tumor weight and enhanced CD4 and CD8 T-cell infiltration þ Results: Parenchymal PMN-MDSC have a positive correlation in a Renca murine model, suggesting that CXCR2 PMN- with IL1b, IL8, CXCL5, and Mip-1a, and I-MDSC correlate with MDSC are important in reducing activity of anti-PD1 antibody. IL8 and CXCL5. Furthermore, peripheral PMN-MDSC correlate Finally, anti-IL1b decreases MDSC and delayed tumor with tumor grade. Given that PMN-MDSC express CXCR2 and growth, suggesting a potential target for MDSC inhibition. parenchymal PMN-MDSC correlated with IL8 and CXCL5, we Clin Cancer Res; 1–10. Ó2016 AACR. Introduction development and subsequent approval of several targeted ther- apies (2). It is well established that tumor-mediated immuno- Renal cell carcinoma (RCC) accounted for 3.8% of newly suppression of the microenvironment and immunoevasion con- diagnosed cancers in the United States in 2014, with close to tribute to decreased clinical efficacy of immune and targeted 64,000 new cases diagnosed (SEER data), which indicates a therapy (3–5). Along with checkpoint blockade of T-cell function consistent increase in the incidence rate since 1975 (1). The (6), multiple cell types are involved in tumor-mediated immu- discovery that biallelic loss of the von Hippel Lindau (VHL) nosuppression, including type 2 natural killer T (NKT) cells, tumor suppressor gene results in increased transcription of growth tumor-associated macrophages (TAM), regulatory T cells (Treg), factors involved in RCC tumorigenesis has resulted in a major and myeloid-derived suppressor cells (MDSC; refs. 7, 8). MDSC paradigm shift in the landscape of RCC treatment, with the are a heterogeneous cell population that is thought to play a major role in tumor-mediated immunoevasion; they arise from myeloid 1Department of Hematology-Oncology, University of Pittsburgh Cancer Institite, progenitor cells that fail to differentiate into mature dendritic Pittsburgh, Pennsylvania. 2Department of Immunology, Cleveland Clinic Foun- cells, granulocytes, or macrophages and are distinguished by the dation, Cleveland, Ohio. 3Department of Quantitative Health Sciences, Cleveland capacity to suppress T-cell and NK cell function (8, 9). That MDSC Clinic Foundation, Cleveland, Ohio. 4Cleveland Clinic Foundation, Taussig Can- use several mechanisms to suppress antitumor immunity has 5 cer Center, Cleveland, Ohio. Pathology Institute, Cleveland Clinic, Cleveland, been demonstrated both in vitro and in vivo. These mechanisms 6 Ohio. Department of Urology, Cleveland Clinic Foundation, Cleveland, Ohio. include cysteine sequestration to decrease proliferation, activa- 7Division of Hematology-Oncology, Mayo Clinic, Scottsdale, Arizona. tion, and differentiation of T cells (8), depletion of L-arginine to þ Corresponding Author: C. Marcela Diaz-Montero, Department of Immunology, arrest T cells in mitosis (10), induction of FoxP3 Treg cells (11), Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH downregulation of CD4 and CD8 T-cell homing to lymph nodes, 44195. Phone: 216-445-7697; Fax: 216-444-9329; E-mail: [email protected] and conversion of antitumor M1 cells into tumor-promoting M2 doi: 10.1158/1078-0432.CCR-15-1823 cells (12). MDSC also promote the tumor vasculature via their Ó2016 American Association for Cancer Research. production of different angiogenic proteins (13, 14). MDSC in www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst October 31, 2016; DOI: 10.1158/1078-0432.CCR-15-1823 Najjar et al. MDSC are induced by chronic inflammation, and inflamma- Translational Relevance tory factors, such as IL6 (25), IL1b (26, 27), GM-CSF (28), We show that total myeloid-derived suppressor cell S100A8/S9A, and prostaglandin E2 (29), have been shown to (MDSC), polymorphonuclear (PMN-MDSC), and imma- promote MDSC accumulation. While associations have been ture MDSC (I-MDSC) in the periphery of patients with renal shown between MDSC and various chemokines in the periphery cell carcinoma (RCC) are increased compared with normal of murine and human cancer hosts, little is known about the controls and that PMN-MDSC correlate with grade, which factors that draw MDSC directly into the tumor parenchyma, if validated in a larger cohort, could represent a prognostic including human RCC. marker. Furthermore, we show that parenchymal PMN- The chemokine receptor CXCR2 is a key mediator of neu- MDSC have a positive correlation with IL8, CXCL5, Mip- trophil migration (30, 31), and its ligands, IL8 and CXCL5, 1a,andIL1b and I- MDSC correlate positively with IL8 have been shown to be chemoattractants for PMN-MDSC and CXCL5. We also show that in a Renca murine model, (32–37). CXCR2 is known to be an important chemokine þ treatment with CXCR2 antagonist increased CD4 and receptor that directs the recruitment of tumor promoting leu- þ CD8 T-cell infiltration and enhanced the efficacy of anti- kocytes into tissue and the inhibition of this receptor signi- PD1 antibody, an important finding in the era of checkpoint ficantly suppresses inflammation-driven and spontaneous tu- inhibitors. Furthermore, IL1b blockade resulted in de- morigenesis (38, 39). In established murine tumors, blocking À À creased parenchymal PMN-MDSC, peripheral PMN, and of CXCR2 using cxcr2 / mice or by treating with cxcr2 anti- monocytic MDSC (M-MDSC) and decreased tumor progres- bodies/antagonists promotes tumor regression and enhances sion. This suggests that anti-IL1b may be a potential strategy anti-PD1 efficacy of blockade-mediated immunotherapy (32, to target immune inhibitory MDSC. These findings warrant 40). Mip-1a is a ligand of CCR5, which is known to be involved further investigation as methods of enhancing the efficacy of in acute inflammation and recruitment and activation of neu- immunotherapy in patients with RCC. trophils (33–35). Finally, MCP-1 is a ligand of CCR2, which is þ known to recruit CD11bGr1 MDSC into tumors (41). Little is known about factors that draw I-MDSC into human tumor parenchyma. In addition, it is known that IL1b induces inflam- mation, leading to the production of chemoattractants for þ þ humans are broadly characterized as expressing CD33 , CD11b , MDSC, including PMN-MDSC, such as IL8 (42). À and HLA-DRlow/ , and multiple MDSC populations have been Here, we analyzed the relationship between circulating or described in patients with solid tumors. Polymorphonuclear intratumoral levels of MDSCs and tumor grade, stage, and RFS MDSC (PMN-MDSC) additionally express CD15 and are in patients with RCC. In addition, we determined whether a CD14-negative, whereas monocytic MDSC (M-MDSC) express correlation exists between these parenchymal/peripheral blood CD14 and not CD15. Immature MDSC (I-MDSC) express neither MDSC subsets and levels of IL1b, IL8, CXCL5, Mip-1a, MCP-1, CD14 nor CD15 (8, 15). and Rantes in the parenchyma and peripheral blood in patients Peripheral MDSC levels are significantly increased in patients with primary RCC tumors, before patients receiving any treat- with cancer and correlate with metastatic burden, clinical ment, to elucidate some of the factors that might promote MDSC cancer stage, and outcome. In a study of 106 patients with accumulation, particularly the PMN-MDSC subset, as it is the solid malignancies (although this did not include patients with largest population in patients with RCC. In addition, the expres- RCC), circulating MDSC correlated with clinic stage and tumor sion of the chemokine receptor CXCR2 on human and mouse burden (16). While PMN-MDSC, M-MDSC, and I-MDSC have PMN-MDSC was examined along with testing the possibility that þ been described in patients with RCC, PMN-MDSC are the CXCR2 myeloid cells promote tumor growth dominant population in peripheral blood of many different types of cancer, including RCC (17, 18). A recent study iden- tified 6 MDSC phenotypes in patients with RCC, 5 of which Materials and Methods were increased in the periphery compared with healthy donors; Tumor lysates the monocytic and PMN-MDSC subtypes correlated with over- Primary RCC tumor samples were collected from 48 patients all survival (19). Indeed, of all the described MDSC subsets, prior to nephrectomy, in accordance with an institutional IRB- only 3 have been shown to correlate with clinical outcomes in approved protocol.
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