Mechanism of ultraviolet radiation induced immune tolerance

紫外线诱导免疫耐受的机制

• 批准号: 10478907
• 负责人: Hui Xu
• 金额: $ 32.34万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-07 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478907
• 关键词: American Cancer Society; Antigen-Presenting Cells; Antitumor Response; Cell Aging; Cells; Chronic; DNA Damage; DNA Repair; Data; Development; Disease; Environment; Exposure to; Haptens; Human; ITGAM gene; Immune; Immune Tolerance; Immune checkpoint inhibitor; Immune response; Immunologic Surveillance; Immunologics; Immunosuppression; Immunotherapy; Impairment; In Vitro; Infiltration; Inflammation Mediators; Interleukin-17; Lead; Link; Malignant Neoplasms; Mediating; Metals; Molecular; Mus; Myeloid Cells; Nature; PD-1 blockade; PD-1/PD-L1; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Photosensitivity; Phototherapy; Population; Predisposition; Prevention; Regulation; Regulatory T-Lymphocyte; Risk; Risk Factors; Role; Skin; Skin Cancer; Skin Neoplasms; Skin tanning; Source; Sunlight; Time; Tissues; Tumor Immunity; Tumor Promotion; UV Radiation Exposure; UV carcinogenesis; UV induced; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Ultraviolet Therapy; Welding; Work; anti-PD-L1 antibodies; carcinogenesis; cell growth; cell injury; clinical application; effector T cell; immunogenic; in vivo; inhibiting antibody; keratinocyte; mutant; novel; organ transplant recipient; prevent; programmed cell death ligand 1; recruit; senescence; solar ultraviolet radiation; translational potential; tumor; tumor-immune system interactions; ultraviolet

In humans, as in mice, chronic exposure to ultraviolet radiation B (UVB, 290-320 nm) impairs host immune responses in addition to inducing mutant cells. Tumors will occur only when there are mutant cells in an immune suppressive environment. In fact, organ transplant recipients who are treated with immunosuppressive medications have a greatly increased risk (up to 100 times) of skin cancers and the tumors that do develop behave more aggressively. It has been known that UVB induced DNA damage is a trigger for immune tolerance. Cell senescence is a protective mechanism to prevent transformation and growth of cells with DNA damage. Senescent cells can produce many inflammatory mediators, a phenomenon called senescence associated secretory phenotype (SASP). SASP recruits and activates immune cells to eliminate DNA damaged cells, which is a critical mechanism of immune surveillance. However, SASP also has roles in immunosuppression and tumor promotion. It is known that UVB induces cell senescence and SASP. However, it is not known whether SASP is a mechanism for UVB induced tolerance. Our studies show that depletion of senescent cells diminishes UVB induced SASP and inhibits tolerance. The result reveals a previously unrecognized mechanism for UVB induced tolerance. Further, we have found that CD11b+/PD-L1+ cells are significantly increased by UVB whereas they are reduced by depletion of senescent cells. Importantly, treatment with anti-PD-L1 antibodies inhibits UVB induced tolerance. To our best knowledge, this is the first evidence that PD-1/PD-L1 checkpoint inhibitor has a role in UVB induced tolerance. Our hypothesis is that UVB induced cell senescence and SASP are a novel mechanism for UVB induced tolerogenic antigen presenting cells (APC), Treg cells, and immune tolerance. Aim 1 will examine mechanisms by which depletion of senescent cells inhibits UVB induced tolerance and immune suppressive environments in skin. We will examine whether depletion of senescent cells inhibits Treg cells and enhances effector T cells. Further studies will determine whether SASP mediated recruitment and stimulation of myeloid cells is a mechanism for UVB induced tolerogenic APC and tolerance. We will also examine whether UVB induced SASP is associated with tolerance in humans. Aim 2 will determine a novel role of IL-17 in UVB induced SASP and carcinogenesis. We will determine whether IL-17 is a component and an upstream regulator of UVB induced SASP and examine molecular mechanisms by which IL-17 regulates SASP. Further studies will examine whether blockade of IL-17 diminishes the susceptibility of mice to photocarcinogenesis. Aim 3 will determine whether CD11b+/PD-L1+ cells are specific tolerogenic APC for the induction of Treg cells and tolerance and whether blockade of PD- 1/PD-L1 reverses established immune tolerance in UVB-tolerized mice. Further studies will examine whether blockade of PD-1/PD-L1 inhibits photocarcinogenesis and whether a combination with neutralizing IL-17 enhances the efficacy of immunotherapy for UVB induced skin tumors.

在人类中，就像在小鼠中一样，长期暴露在紫外线B(UVB，290-320 nm)中会损害宿主 除了诱导突变细胞外，还有免疫反应。只有当有突变细胞时才会发生肿瘤 在免疫抑制的环境中。事实上，接受器官移植治疗的人 免疫抑制药物极大地增加了患皮肤癌的风险(高达100倍)， 确实发展起来的肿瘤表现得更具侵略性。已知中波紫外线诱导的DNA损伤是一种 触发免疫耐受。细胞衰老是防止转化和生长的一种保护机制 有DNA损伤的细胞。衰老细胞可以产生许多炎症介质，这种现象被称为 衰老相关分泌表型(SASP)。SASP招募并激活免疫细胞以 清除DNA损伤的细胞，这是免疫监测的关键机制。然而，SASP也有 在免疫抑制和肿瘤促进中的作用。已知UVB可诱导细胞衰老和SASP。 然而，SASP是否是UVB诱导耐受的一种机制尚不清楚。我们的研究表明 衰老细胞的耗竭减少了UVB诱导的SASP并抑制了耐受性。结果显示， UVB诱导耐受的机制此前未知。此外，我们发现CD11b+/PD-L1+ UVB可显着增加细胞数量，而衰老细胞则减少。重要的是 用抗PD-L1抗体治疗可抑制UVB诱导的耐受。据我们所知，这是第一次 有证据表明PD-1/PD-L1检查点抑制物在UVB诱导的耐受中起作用。我们的假设是 UVB诱导细胞衰老和SASP是UVB诱导耐受抗原的一种新机制 提呈细胞(APC)、Treg细胞和免疫耐受。目标1将检查耗尽的机制 的衰老细胞抑制紫外线诱导的耐受性和皮肤的免疫抑制环境。我们会 检查衰老细胞的耗尽是否抑制Treg细胞和增强效应器T细胞。进一步研究 将确定SASP介导的髓系细胞募集和刺激是否是UVB的一种机制 诱导耐受性APC和耐受性。我们还将研究UVB诱导的SASP是否与 人类的耐受性。目的探讨IL-17在UVB诱导SASP致癌中的新作用。我们 将确定IL-17是否是UVB诱导的SASP的组成部分和上游调节因子，并检查 IL-17调节SASP的分子机制。进一步的研究将检查是否阻断IL-17 降低小鼠对光致癌的敏感性。AIM 3将确定CD11b+/PD-L1+ 细胞是特异的致耐受APC，用于诱导Treg细胞和耐受，以及是否阻断PD- 1/PD-L1逆转UVB耐受小鼠已建立的免疫耐受。进一步的研究将检查是否 阻断PD-1/PD-L1抑制光癌发生及其与中和IL-17的联合作用 提高UVB诱导的皮肤肿瘤的免疫治疗效果。