Najjar Yana G, Rayman Patricia, Jia Xuefei, Pavicic Paul G, Rini Brian I, Tannenbaum Charles, Ko Jennifer, Haywood Samuel, Cohen Peter, Hamilton Thomas, Diaz-Montero C Marcela, Finke James
Department of Hematology-Oncology, University of Pittsburgh Cancer Institite, Pittsburgh, Pennsylvania.
Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio.
Clin Cancer Res. 2017 May 1;23(9):2346-2355. doi: 10.1158/1078-0432.CCR-15-1823. Epub 2016 Oct 31.
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. 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. 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. 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. .
关于肾细胞癌（RCC）患者骨髓来源的抑制性细胞（MDSC）亚群与各种趋化因子之间的关联，以及将MDSC吸引至肿瘤实质的因素，目前所知甚少。我们分析了48例RCC患者在肾切除术中从肿瘤实质和外周血中分离出的多形核MDSC（PMN-MDSC）、单核细胞MDSC（M-MDSC）和未成熟MDSC（I-MDSC）。我们分析了白细胞介素1β（IL1β）、白细胞介素8（IL8）、CXC趋化因子配体5（CXCL5）、巨噬细胞炎性蛋白-1α（Mip-1α）、单核细胞趋化蛋白-1（MCP-1）和调节激活正常T细胞表达和分泌因子（Rantes）的水平。此外，我们在Renca小鼠模型中进行实验，以评估CXCR2与抗程序性死亡蛋白1（anti-PD1）之间的治疗协同作用，并阐明IL1β阻断对MDSC的影响。肿瘤实质中的PMN-MDSC与IL1β、IL8、CXCL5和Mip-1α呈正相关，I-MDSC与IL8和CXCL5相关。此外，外周血PMN-MDSC与肿瘤分级相关。鉴于PMN-MDSC表达CXCR2，且肿瘤实质中的PMN-MDSC与IL8和CXCL5相关，我们评估了单独或联合抗PD1阻断CXCR2的反应。联合治疗可减轻肿瘤重量，并增强CD4和CD8 T细胞浸润。此外，抗IL1β可减少外周血中的PMN-MDSC和M-MDSC、肿瘤中的PMN-MDSC以及外周血中的CXCL5和角质形成细胞趋化因子（KC）。抗IL1β还可延缓肿瘤生长。肿瘤实质中的PMN-MDSC与IL1β、IL8、CXCL5和Mip-1α呈正相关，表明它们可能将PMN-MDSC吸引至肿瘤中。外周血PMN-MDSC与肿瘤分级相关，提示其具有预后意义。在Renca小鼠模型中，抗CXCR2和抗PD1协同作用可减轻肿瘤重量，并增强CD4和CD8 T细胞浸润，表明CXCR2 PMN-MDSC在降低抗PD1抗体活性方面很重要。最后，抗IL1β可减少MDSC并延缓肿瘤生长，提示其可能是抑制MDSC的潜在靶点。
