Myeloid-Derived Suppressor Cell Subset Accumulation in Renal Cell Carcinoma Parenchyma Is Associated with Intratumoral Expression of IL1β, IL8, CXCL5, and Mip-1α.
Myeloid-Derived Suppressor Cell Subset Accumulation in Renal Cell Carcinoma Parenchyma Is Associated with Intratumoral Expression of IL1β, IL8, CXCL5, and Mip-1α.
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DOI：
10.1158/1078-0432.ccr-15-1823
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发表时间：
2017-05-01
期刊：
影响因子：
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通讯作者：
Finke J
中科院分区：
文献类型：
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作者：
Najjar YG;Rayman P;Jia X;Pavicic PG Jr;Rini BI;Tannenbaum C;Ko J;Haywood S;Cohen P;Hamilton T;Diaz-Montero CM;Finke J
对于小细胞癌患者中MDSC亚群与各种趋化因子之间的关系，或将MDSC带入肿瘤实质的因素，我们知之甚少。我们分析了48例肾切除术后分离的肾细胞癌患者的实质和外周血中的PMN-MDSC、M-MDSC和I-MDSC。我们分析了IL-1β、IL-8、CXCL5、Mip-1α、MCP-1和Rantes的水平。此外，我们在Renca小鼠模型中进行了实验，以评估CXCL2和抗pd1之间的治疗协同作用，并阐明IL-1β阻断对MDSC的影响。实质PMN-MDSC与IL-1β、IL-8、CXCL-5、Mip-1α呈正相关，I-MDSC与IL-8、CXCL-5呈正相关。此外，外周PMN-MDSC与肿瘤分级相关。考虑到PMN-MDSC表达CXCR2，并且实质PMN-MDSC与IL-8和CXCL5相关，我们评估了有或没有抗pd1阻断CXCR2的反应。联合治疗可降低肿瘤重量，增强CD4+和CD8+ T细胞浸润。此外，抗il - 1β可降低外周PMN-MDSC和M-MDSC，降低肿瘤内PMN-MDSC，降低外周CXCL5和KC，延缓肿瘤生长。实质PMN-MDSC与IL-1 β、IL-8、CXCL-5和Mip-1α呈正相关，提示它们可能吸引PMN-MDSC进入肿瘤。外周PMN-MDSC与肿瘤分级相关，提示预后意义。在Renca小鼠模型中，抗CXCR2和抗pd1协同降低肿瘤重量，增强CD4+和CD8+ T细胞浸润，提示CXCR2+ PMN-MDSC在降低抗pd -1抗体活性中起重要作用。最后，抗il - 1β降低MDSC并延迟肿瘤生长，提示MDSC抑制的潜在靶点。
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. 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. 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. 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.