Type I Interferon Regulation of PD-L1 Expression and Function in MDSCs

I 型干扰素对 MDSC 中 PD-L1 表达和功能的调节

• 批准号: 10417046
• 负责人: KEBIN LIU
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417046
• 关键词: Cancer Patient; Cell Differentiation process; Chronic; Colon Carcinoma; Colorectal Cancer; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; General Population; Goals; Human; IFNAR1 gene; Immune; Immune checkpoint inhibitor; Immunosuppression; Immunotherapy; In Vitro; Interferon Type I; Interferon Type II; Interferons; Ligands; Lymphocyte Activation; Lymphocyte Suppression; Mediating; Modeling; Molecular; Molecular Target; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Pathologic; Pathway interactions; Physiological; Play; Population; Population Heterogeneity; Regulation; Reporting; Resistance; Role; STAT1 gene; STAT2 gene; Signal Pathway; Stat3 Signaling Pathway; Survival Rate; T-Cell Activation; T-Lymphocyte; Testing; Time; Tumor Escape; Up-Regulation; Veterans; aged; anti-PD-1; autocrine; base; colon cancer patients; colon cancer progression; granulocyte; in vivo; lymphoid neoplasm; macrophage; neoplastic cell; novel; programmed cell death ligand 1; targeted treatment; tumor; tumor microenvironment; tumor progression

Project Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells (IMCs). Under physiological conditions, IMCs quickly differentiate into mature granulocytes, macrophages or dendritic cells. By contrast, under pathological conditions, a partial block of IMC differentiation into mature myeloid cells results in the expansion and activation of this population. In human cancer patients, massive accumulation of MDSCs is a hallmark of cancer progression. One key function of MDSCs is to inhibit activation of cytotoxic T lymphocytes (CTLs) through multiple suppressive mechanisms. PD-L1 has emerged as a new immune suppressive factor of MDSCs. However, the function of MDSC-expressed PD-L1 in suppression of CTL activation in the tumor microenvironment is currently controversial. Our preliminary studies determined for the first time that type I IFNs regulate constitutive PD-L1 expression in MDSCs in an autocrine manner. We further determined that IFNAR1 controls PD-L1 expression level in MDSCs in the tumor microenvironment. Therefore, type I IFNs might play a dominant role over IFNγ in up-regulating PD-L1 expression in MDSCs in the tumor microenvironment, which remains to be determined. Our central hypothesis is that type I IFNs regulate PD-L1 expression in tumor-infiltrating MDSCs and both tumor-expressed and MDSC-expressed PD-L1 contributes to CTL suppression and tumor immune evasion in human colon cancer. The objectives are: 1) elucidate the molecular mechanism underlying PD-L1 expression regulation by type I IFNs in MDSCs; 2) Determine the relative contributions of tumor-expressed and MDSC-expressed PD-L1 in suppression of CTL activation and tumor immune evasion; and 3) Test the hypothesis that type I IFN regulates PD-L1 expression in MDSCs in human colon cancer patients. Successful completion of the proposed studies will determine the function of MDSC-expressed PD-L1 in immune suppression and tumor immune evasion in human colorectal cancer patients and identify novel molecular target to enhance the efficacy of checkpoint inhibitor immunotherapy in human colon cancer.

项目摘要 髓源性抑制细胞（MDSC）是一种异质性的未成熟髓系细胞群 （IMCs）。在生理条件下，IMC快速分化为成熟的粒细胞、巨噬细胞或巨噬细胞。 树突状细胞相比之下，在病理条件下，部分阻断IMC向成熟的分化， 骨髓细胞导致该群体的扩增和活化。在人类癌症患者中， MDSC的积累是癌症进展的标志。MDSC的一个关键功能是抑制 细胞毒性T淋巴细胞（CTL）通过多种抑制机制。PD-L1已经成为一种新的 MDSC的免疫抑制因子。然而，MDSC表达的PD-L1在抑制CTL中的功能是不确定的。 肿瘤微环境中的激活目前是有争议的。我们的初步研究确定， I型IFN首次以自分泌方式调节MDSC中的组成型PD-L1表达。我们进一步 确定IFNAR 1控制肿瘤微环境中MDSC中的PD-L1表达水平。因此，我们认为， I型IFN可能在上调肿瘤MDSC中PD-L1表达方面比IFNγ起主导作用 微环境，有待确定。我们的中心假设是I型干扰素调节PD-L1 在肿瘤浸润性MDSC中的表达以及肿瘤表达和MDSC表达的PD-L1都有助于 人结肠癌中的CTL抑制和肿瘤免疫逃避。目的是：1）阐明 MDSC中I型IFN调控PD-L1表达的分子机制; 2）确定MDSC中I型IFN对PD-L1表达的影响。 肿瘤表达和MDSC表达的PD-L1在抑制CTL活化中的相对作用， 肿瘤免疫逃避;和3）检验I型IFN调节PD-L1在MDSC中表达的假设， 人类结肠癌患者。成功完成拟议的研究将决定 MDSC表达的PD-L1在结直肠癌患者免疫抑制和肿瘤免疫逃避中的作用 并鉴定新的分子靶点以增强检查点抑制剂免疫疗法在人结肠中的功效 癌