Regulation of MDSC function and trafficking

MDSC 功能和运输的调节

• 批准号: 8606201
• 负责人: JAMES H FINKE
• 金额: $ 36.55万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606201
• 关键词: Address; Adoptive Transfer; Animal Model; Animals; Blood; Blood Vessels; Blood specimen; Bone Marrow; CSF3 gene; Cancer Patient; Cell physiology; Cells; Development; Dioxygenases; Disease; Disease Outcome; Engineering; Environment; Gene Expression; Gene Expression Profile; Granulocyte-Macrophage Colony-Stimulating Factor; Histologic; Human; IL8RB gene; ITGAM gene; Immune; Immunosuppression; Immunosuppressive Agents; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Infiltrate; Interleukin-1; Interleukin-6; Lead; Leukocytes; Ligands; MMP8 gene; MMP9 gene; Malignant Neoplasms; Modeling; Molecular Profiling; Mus; Myelogenous; Myeloid Cells; Neutralization Tests; Pathway interactions; Patients; Phenotype; Population; Population Heterogeneity; Production; Proteins; Recruitment Activity; Regulation; Relative (related person); Renal Cell Carcinoma; Reporting; Role; Sampling; Shapes; Site; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Testing; Therapeutic Intervention; Tissue Sample; Tube; Tumor Immunity; Tumor Tissue; Tumor-Derived; angiogenesis; arginase; chemokine; chemokine receptor; cytokine; human NOS2A protein; in vitro testing; indolamine; migration; neutralizing antibody; new therapeutic target; programs; public health relevance; receptor expression; therapeutic target; trafficking; tumor; tumor growth; tumor microenvironment; tumor progression

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.

描述（由申请方提供）：髓源性抑制细胞（MDSC）是一种不同的未成熟粒细胞和单核细胞群体，可浸润人和鼠肿瘤并加重疾病。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，表明更多的促炎性肿瘤可以通过激活增强MDSC扩增的细胞因子、其向肿瘤的募集以及其血管生成和免疫抑制效应分子的表达增加来积极促进其自身的进展。我们发现粒细胞（G）和单核细胞（M）MDSC群体在趋化因子受体表达方面都是异质的，其中不同的子集高度富集免疫抑制和/或血管生成分子的表达，使它们成为潜在的重要治疗靶点。这对于单独表达CXCR 2或与其他趋化因子受体联合表达CXCR 2的G-MDSC和M-MDSC亚群尤其如此。浸润炎性鼠肿瘤的免疫抑制性和血管生成性G-MDSC的这种丰度在人肾细胞癌（RCC）肿瘤中是不稳定的，其也主要积聚G-MDSC。我们提出炎症通过多种途径促进肿瘤进展，包括诱导BM中CXCR 2群体内的免疫抑制和促血管生成基因表达程序，调节控制MDSC从骨髓运输到肿瘤的CXCR 2趋化因子/趋化因子受体轴，以及在CXCR 2 + MDSC到达肿瘤组织内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，以测试我们的假设，使用几种动物肿瘤模型（Renca，SIRCC，4 T1，B16和CT 26）沿着血液和肿瘤样本的肾细胞癌（RCC）患者。在这里，我们将：1）鉴定负责具有肿瘤促进活性的CXCR 2 + MDSC积累的细胞因子。2)将CXCR 2/趋化因子受体轴的作用定义为引发最具血管生成性、免疫抑制性和疾病促进性的MDSC亚群至肿瘤的不可或缺的部分。3)评估肿瘤微环境对浸润MDSC亚群免疫抑制和促血管生成基因表达谱的影响。这些研究的结果应将CXCR 2 + G-MDSC和较小程度的M-MDSC鉴定为在某些炎性肿瘤如人RCC中促进免疫抑制和血管生成的重要群体。确定参与促进CXCR 2 + MDSC优势的趋化因子和细胞因子可能会导致新的治疗靶点。