Role of cDC2 subsets in host protection and CD4T cell responses in melanoma

cDC2亚群在黑色素瘤宿主保护和CD4T细胞反应中的作用

基本信息

批准号：
10331077
负责人：
YOSUKE KUMAMOTO
金额：
$ 17.44万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10331077
关键词：
Address Affect Antibodies Antigens Applications Grants Binding Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Data Dendritic Cells Dermal Effector Cell Evolution Future Gene Expression Genes Goals Heterogeneity Homologous Gene Human Immune response Immunity Immunologics Immunotherapy Lead Leukocytes Measures Modeling Molecular Molecular Profiling Mus Pathway interactions Patients Phase Phenotype Play Population Population Sizes Research Role Skin T-Cell Activation T-Lymphocyte Techniques Testing Tumor Immunity adaptive immune response adaptive immunity base cell type cytotoxic differential expression draining lymph node experimental study immunogenic in vivo lung colonization lymph nodes mRNA Expression melanoma mouse model new therapeutic target novel recruit response single-cell RNA sequencing success therapeutic target transcriptomics tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

Project Summary Despite recent successes, many melanoma patients still fail to respond to immunotherapy and there is a pressing need for identifying novel therapeutic targets. The primary goal of immunotherapy is to activate tumor- specific immune responses, in which tumor-specific T cells play a crucial role. Although cytotoxic CD8T cells have long been the main focus of research on tumor-specific immunity, growing evidence shows the contribution of CD4T cells to tumor rejection, especially in tumors treated with immunogenic therapy. However, the mechanism of CD4T cell activation in melanoma is less well understood compared to that of CD8T cells. Type 2 conventional dendritic cells (cDC2s) have high antigen presenting capacity to activate antigen-specific CD4T cells, but their role in tumor immunity has not been fully understood due partially to the phenotypic heterogeneity within this cell type. We previously identified CD301b+ DCs as the major cDC2 population in the mouse skin and showed that they transport antigens from the skin to the draining lymph node and efficiently prime antigen-specific CD4T cells. This proposal focuses on understanding their role in host protection and CD4T cell activation in experimental melanoma models in mice. To understand how cDC2 cells respond to the tumor microenvironment at the molecular level, we employ a novel technique of single-cell RNA sequencing to identify subset-specific gene expression changes in cDC2 subsets during melanoma progression. In parallel, we use targeted cell depletion approaches to identify the cellular mechanisms of cDC2-depedent host protection in both untreated melanoma as well as in those treated with immunogenic therapy. These experiments will collectively provide comprehensive understanding on the role of cDC2 subsets in melanoma and potentially reveal new cellular pathways that lead to activation of melanoma-specific CD4T cells.

项目概要尽管最近取得了成功，但许多黑色素瘤患者仍然对免疫疗法没有反应，并且存在迫切需要确定新的治疗靶点。免疫治疗的主要目标是激活肿瘤特异性免疫反应，其中肿瘤特异性 T 细胞发挥着至关重要的作用。尽管CD8T细胞具有细胞毒性长期以来，肿瘤特异性免疫研究的主要焦点是，越来越多的证据表明 CD4T细胞对肿瘤排斥的贡献，特别是在接受免疫原性治疗的肿瘤中。然而，与 CD8T 细胞相比，黑色素瘤中 CD4T 细胞激活的机制尚不清楚。 2 型常规树突状细胞 (cDC2) 具有高抗原呈递能力，可激活抗原特异性 CD4T 细胞，但其在肿瘤免疫中的作用尚未完全了解，部分原因是表型该细胞类型内的异质性。我们之前将 CD301b+ DC 确定为主要的 cDC2 群体小鼠皮肤，表明它们能够有效地将抗原从皮肤转运到引流淋巴结引发抗原特异性 CD4T 细胞。该提案的重点是了解它们在宿主保护和小鼠实验性黑色素瘤模型中 CD4T 细胞的激活。了解 cDC2 细胞如何响应为了在分子水平上研究肿瘤微环境，我们采用了单细胞RNA测序的新技术识别黑色素瘤进展过程中 cDC2 子集中的子集特异性基因表达变化。并联，我们使用靶向细胞耗竭方法来识别 CDC2 依赖性宿主的细胞机制对未经治疗的黑色素瘤以及接受免疫原性治疗的黑色素瘤均具有保护作用。这些实验将共同全面了解 cDC2 子集在黑色素瘤中的作用并有可能揭示导致黑色素瘤特异性 CD4T 细胞激活的新细胞途径。