Regulation of MDSC function and trafficking

描述(申请人提供)：髓源性抑制细胞(MDSC)是一组不同的未成熟粒细胞和单核细胞，可渗透到人类和小鼠肿瘤并加重疾病。越来越多的证据，包括我们在小鼠和人类肿瘤中的初步发现表明，更多的促炎肿瘤可以通过激活细胞因子来促进其自身的进展，这些细胞因子促进了MDSC的扩张，促进了它们对肿瘤的募集，并增加了血管生成和免疫抑制效应分子的表达。我们发现粒细胞(G)和单核细胞(M)MDSC群体在趋化因子受体的表达方面都是异质性的，其中不同的亚群高度富含免疫抑制和/或血管生成分子的表达，使它们成为潜在的重要治疗靶点。对于单独或与其他趋化因子受体联合表达CXCR2的G-MDSC和M-MDSC亚群尤其如此。这种大量的免疫抑制和血管生成的G-MDSCs渗透到炎症性小鼠肿瘤中，在人类肾细胞癌(RCC)肿瘤中是平行的，后者也积聚了大部分G-MDSCs。我们认为，炎症通过多种途径促进肿瘤进展，包括在骨髓中CXCR2群体内诱导免疫抑制和促血管生成基因表达程序，调节控制MDSCs从骨髓向肿瘤转运的CXCR2趋化因子/趋化因子受体轴，以及CXCR2+MDSCs到达肿瘤组织后对其表型和功能活性的调节。我们提出了三个具体的目标来验证我们的假设，使用几个动物肿瘤模型(RencA，SIRCC，4T1，B16和CT26)以及来自肾癌患者的血液和肿瘤样本。在这里，我们将：1)确定与CXCR2+MDSC积聚有关的具有促肿瘤活性的细胞因子。2)确定CXCR2/趋化因子受体轴在诱导最具血管生成、免疫抑制和促进疾病的MDSC亚群到肿瘤中的作用是不可或缺的。3)评估肿瘤微环境在形成浸润性MDSC亚群免疫抑制和促血管生成基因表达谱中的影响。这些研究的结果应该确定CXCR2+G-MDSC和M-MDSC是促进某些炎症性肿瘤(如人肾细胞癌)免疫抑制和血管生成的关键群体。明确参与促进CXCR2+MDSC优势的趋化因子和细胞因子可能会导致新的治疗靶点。

DESCRIPTION (provided by applicant): Myeloid derived suppressor cells (MDSC) are a diverse population of immature granulocytic and monocytic cells that infiltrate human and murine tumors and exacerbate disease. A growing body of evidence including our preliminary findings in both mouse and human tumors suggests that it is the more proinflammatory tumors that can aggressively promote their own progression by activating cytokines that enhance MDSC expansion, their recruitment to tumor, and their increased expression of angiogenic and immunosuppressive effector molecules. We find that both the granulocytic-(G) and monocytic-(M) MDSC populations are heterogenous with respect to chemokine receptor expression where distinct subsets are highly enriched for expression of immunosuppressive and/or angiogenic molecules, rendering them potentially important therapeutic targets. This is particularly true for G-MDSC- and M-MDSC subpopulations expressing CXCR2 either alone or in conjunction with other chemokine receptors. This abundance of immunosuppressive- and angiogenic G-MDSCs that infiltrate inflammatory murine tumors is paralleled in human renal cell carcinoma (RCC) tumors, which also accumulate mostly G-MDSCs. He we propose that inflammation promotes tumor progression through multiple pathways including induction of immunosuppressive and pro-angiogenic gene expression programs within the CXCR2 populations in the BM, modulation of the CXCR2 chemokine/chemokine receptor axes that control the trafficking of MDSCs from the bone marrow to the tumor, and regulation of the phenotype and functional activity of the CXCR2+ MDSCs after their arrival within the tumor tissue. We propose three specific aims to test our hypothesis using several animal tumor models (Renca, SIRCC, 4T1, B16 and CT26) along with blood and tumor samples from patients with renal cell carcinoma (RCC). Here we will: 1) Identify the cytokines responsible for the accumulation of CXCR2+ MDSC with tumor promoting activity. 2) Define the role of the CXCR2/chemokine receptor axis as being integral for eliciting the most angiogenic, immunosuppressive and disease-promoting MDSC subpopulations to tumors. 3) Assess the impact that the tumor microenvironment has in shaping the immunosuppressive and proangiogenic gene expression profile of infiltrating MDSC subsets. The findings from these studies should identify CXCR2+ G-MDSC and to a lesser extent M-MDSC as critical populations important in promoting immune suppression and angiogenesis in certain inflammatory tumors such as human RCC. Defining the chemokine and cytokines involved in promoting the dominance of CXCR2+ MDSC may lead to new therapeutic targets.