Regulation of MDSC function and trafficking

MDSC 功能和运输的调节

基本信息

批准号：
9201306
负责人：
JAMES H FINKE
金额：
$ 37.68万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9201306
关键词：
4T1 Address Adoptive Transfer Alpha Cell Animal Model Animals Blood Blood specimen Bone Marrow CSF3 gene CT26 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 Immature Granulocyte Immature Monocyte Immune Immunosuppression Immunosuppressive Agents In Vitro Individual Inflammation Inflammatory Inflammatory Infiltrate Interleukin-1 Interleukin-6 Interleukin-8B Receptor Kidney Neoplasms Lead Leukocytes Ligands MMP8 gene MMP9 gene Malignant Neoplasms Modeling Molecular Profiling Mus Myelogenous Myeloid Cells NOS2A gene Neutralization Tests Pathway interactions Patients Phenotype Population Population Heterogeneity Production Proteins Recruitment Activity Regulation 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 blood vessel development chemokine chemokine receptor cytokine gene product granulocyte in vitro testing indolamine migration monocyte neutralizing antibody new therapeutic target programs public health relevance receptor expression therapeutic target trafficking tumor tumor growth tumor microenvironment tumor progression

项目摘要

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（由申请人提供）：髓样衍生的抑制细胞（MDSC）是多种未成熟的粒细胞和单核细胞的种群，可渗入人和鼠类肿瘤，并加剧症状。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，这表明，促炎性肿瘤可以通过激活细胞因子来积极地促进自己的进展，从而增强MDSC的扩张，对肿瘤的募集以及血管生成和免疫抑制效应分子的表达增加。我们发现，相对于趋化因子受体表达，粒细胞（G）和单核细胞 - （M）MDSC群都是异质的，其中不同的子集高度富集于免疫抑制和/或血管生成分子的表达，从而使它们具有潜在的重要治疗靶标。对于单独或与其他趋化因子受体共同表达CXCR2的G-MDSC和M-MDSC亚群尤其如此。在人肾细胞癌（RCC）肿瘤中平行于浸润炎症性鼠肿瘤的这种免疫抑制和血管生成G-MDSC，它们也主要积累G-MDSC。我们提出，炎症通过多种途径促进肿瘤的进展，包括在BM中CXCR2种群中诱导免疫抑制和促血管生成基因表达程序，调节CXCR2趋化因子/趋化因子受体轴，这些因子/趋化因子受体轴控制了MDSC从骨莫尔（Bone Marrow）和法规的运输中，并将MDSC的运输量和调节作用。到达肿瘤组织内。我们提出了三个特定的目的，旨在使用几种动物肿瘤模型（Renca，SirCC，4T1，B16和CT26）以及来自肾细胞癌（RCC）患者的血液和肿瘤样本进行测试。在这里，我们将：1）确定负责CXCR2+ MDSC积累具有肿瘤活性的细胞因子。 2）将CXCR2/趋化因子受体轴的作用定义为引发最血管生成，免疫抑制和促进疾病的MDSC亚群的组成部分。 3）评估肿瘤微环境在塑造浸润MDSC亚群的免疫抑制和促血管生成基因表达谱的影响。这些研究的发现应确定CXCR2+ G-MDSC，并在较小程度上确定M-MDSC作为关键种群，对于促进某些炎症性肿瘤（例如人类RCC）的免疫抑制和血管生成很重要。定义参与促进CXCR2+ MDSC优势的趋化因子和细胞因子可能导致新的治疗靶标。