ICOSL Signaling in Macrophages Promotes Anti-Tumor Immunity

巨噬细胞中的 ICOSL 信号传导促进抗肿瘤免疫

• 批准号: 10005022
• 负责人: Emma Kurz
• 金额: $ 4.4万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005022
• 关键词: Acceleration; Adaptor Signaling Protein; Address; Adoptive Transfer; Alanine; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Automobile Driving; Back; Binding; Biological Assay; Biology; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cytoplasmic Tail; Cytotoxic T-Lymphocytes; Disease; Disease Progression; Family; Flow Cytometry; Genetic; Growth; Human; Immune; Immune response; Immunosuppression; Immunotherapeutic agent; In Vitro; Incidence; Inflammatory; Knowledge; Ligands; Literature; Long-Term Survivors; Malignant Neoplasms; Malignant neoplasm of pancreas; Maps; Mediating; Molecular; Mus; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Pharmacology; Phenotype; Play; Proteins; Regulation; Regulatory T-Lymphocyte; Role; STAT1 gene; Scanning; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Surface; Survival Rate; T cell differentiation; T cell response; T-Lymphocyte; Testing; Th2 Cells; Tumor Immunity; Tumor-associated macrophages; Tumor-infiltrating immune cells; Up-Regulation; Work; advanced disease; base; combat; cytotoxic; immunogenic; in vivo; inhibitor/antagonist; macrophage; mortality; mouse model; programs; receptor; recruit; single-cell RNA sequencing; transcriptome; tumor; tumor growth; tumor microenvironment; tumor progression

Project Summary/Abstract: Pancreatic ductal adenocarcinoma (PDA) is an aggressive disease for which there are few long-term survivors. The inflammatory tumor microenvironment (TME) is known to influence pancreatic cancer progression by either generating cytotoxic T cell responses, or, more commonly, by inducing tumor-permissive tolerance. Many studies have shown that tumor-associated macrophages, or TAMs, play a vital role in educating T cells toward immunogenic or tolerogenic differentiation in PDA. However, the mechanisms that regulate macrophage phenotype in this disease are not well understood. ICOSL, the cognate ligand for the ICOS co- stimulatory receptor on T cells, is a B7-family 40 kD protein expressed on macrophages. While ICOS signaling has been well-characterized, the concept of ICOSL ‘back-signaling’ into macrophages upon engagement by ICOS has not been well described. My preliminary work indicates that ICOSL is up-regulated on tumor associated macrophages in the context of pancreatic cancer. Genetic deletion or antibody-mediated neutralization of ICOSL on macrophages results in their differentiation toward an alternatively activated M2-like phenotype and acceleration of cancer progression. Conversely, I found that ICOSL engagement or activation in macrophages by treatment with an ICOS Fc leads to a profound immunogenic program in vitro. Mass spectrometric analysis has shown that ICOSL co-precipitates with STAT1 in macrophages, a known driver of M1-like phenotype. However, the specific molecular mechanisms through which ICOSL acts as a regulator of macrophage phenotype and its applicability as a master regulator of anti-tumor immunity in PDA remains unknown. My proposal will attempt to bridge this gap in knowledge through two main specific aims: Aim 1 will seek to determine if ICOSL-mediated tumor protection in PDA is a T-cell dependent phenomenon. Specifically, this aim will explore the effects of ICOSL-activation or neutralization in macrophages on T-cell phenotype; employing flow cytometry, antigen presentation assays, and 10x single cell RNA sequencing of intra-tumoral immune cells from multiple murine models of PDA. Aim 2 will seek to address the specific intracellular signaling mechanisms through which ICOSL regulates macrophage polarization. By employing site directed mutagenesis to map the interaction surface that mediates ICOSL binding to STAT1, this aim will uncover a heretofore unknown signaling pathway that drives immunogenic macrophage programming involving the cytoplasmic tail of ICOSL.

项目总结/文摘: