Cancer Cell Intrinsic Interferon-I pathway Activation by Fractionated Radiation

分段放射激活癌细胞内源性干扰素-I 通路

基本信息

批准号：
10706961
负责人：
Sandra Demaria
金额：
$ 39.71万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-19 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706961
关键词：
Abscopal effect Activated Natural Killer Cell Adaptor Signaling Protein Address Antigens Autoimmunity Automobile Driving Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Circulation Cross Presentation Cytosol DNA DNA Binding DNA Damage DNA Methylation Data Dendritic Cells Disseminated Malignant Neoplasm Distal Dose Exposure to Fostering Generations Goals Growth Factor Home Human Hybrids IFNAR1 gene Immune Immune response Immunotherapy Impairment Infiltration Interferon Activation Interferon Type I Interferon-beta Interferons Intervention Irradiated tumor Knowledge Literature Malignant neoplasm of lung Mediating Mitochondrial DNA Mus Mutation NK Cell Activation Natural Killer Cells Neoplasm Metastasis Nucleic Acids Pathway interactions Patient Selection Patients Phenotype Play Pre-Clinical Model Process Production Publishing RNA Radiation Radiation therapy Role Sampling Second Messenger Systems Serum Signal Transduction Site Stimulator of Interferon Genes Stimulus T cell response T-Cell Activation T-Lymphocyte Testing Tumor Promotion Tumor-infiltrating immune cells Work anti-CTLA-4 therapy cancer cell candidate identification candidate marker cell type checkpoint therapy chemokine effector T cell extracellular vesicles fractionated radiation immune checkpoint blockade immunogenic improved in situ vaccine in vitro testing in vivo ipilimumab knock-down micronucleus novel overexpression patient response pseudotoxoplasmosis syndrome radiation response recruit response single cell analysis tumor tumor microenvironment

项目摘要

Recent evidence indicates that the presence of conventional dendritic cells type 1 (cDC1) in the tumor microenvironment (TME) is required for response to immune checkpoint blockade (ICB) therapy. In addition to cross- presenting cancer cell-derived antigens to CD8+ and CD4+ T cells, cDC1 promote tumor infiltration by effector T cells, and support their survival and function. Thus, interventions that improve cDC1 recruitment to the TME could enhance patient responses to ICB. Focal radiation therapy (RT) increases responses to ICB therapy, at least in part by inducing type I interferon (IFN-I) and driving cDC1 into the irradiated tumor. We have previously shown that cDC1 are essential for immune-mediated regression of irradiated and synchronous non-irradiated tumors (abscopal effect) in mice treated with RT and ICB. Abscopal responses have also been achieved in metastatic cancer patients treated with RT and ICB, but less reliably than expected, and the determinants of such responses remain unclear. We hypothesize that a previously unexplored barrier to abscopal responses is the limited infiltration of poorly immunogenic tumors by cDC1, which precludes effector T cells generated at the irradiated tumor site from rejecting non-irradiated tumors. Moreover, we hypothesize that activation of a strong IFN-I response in the irradiated tumor is essential for achieving systemic activation of natural killer (NK) cells, which can home to non-irradiated tumors and foster the recruitment of cDC1. This hypothesis is supported by a strong scientific premise which is based on the recent literature and on our extensive published and unpublished data, including the fact that increased serum IFNb post-RT was the top predictor for abscopal responses in metastatic lung cancer patients treated with RT+anti-CTLA4 (Nat Med 2018). To test this hypothesis three independent but related aims that address different mechanistic questions are planned. Aim 1 will investigate the role of RNA:DNA hybrids, which accumulate in the cytosol of irradiated cancer cells and in the cargo of small extracellular vesicles (sEV) they produce, in activating the IFN-I pathway via cGAS/STING in cancer cells and locoregional DCs. The role of RT-induced IFNb in systemic NK cell activation will be confirmed by using IFNAR1-deficient NK cells. Aim 2 will determine the contribution of sEV to RT-induced IFN-I activation in vivo by using Rab27a-deficient cancer cells. Aim 3 will directly address the role of NK cells in driving cDC1 infiltration in abscopal tumors and abscopal responses to RT+ICB. In addition, NK cell functional subsets present in the blood of lung cancer patients with abscopal response to RT+anti- CTLA4 will be investigated by single cell analysis. Results of proposed studies will identify a novel mechanism whereby local IFN-I induction by RT activates a systemic cross-talk between NK cells and cDC1, required for T-cell mediated rejection of abscopal tumors.

最近的证据表明，肿瘤中常规的树突状细胞（CDC1）的存在微环境（TME）是对免疫检查点阻滞（ICB）治疗的反应所必需的。除了交叉 CDC1向CD8+和CD4+ T细胞呈现癌细胞衍生的抗原，通过效应T细胞促进肿瘤浸润，并支持其生存和功能。因此，改善CDC1募集到TME的干预措施可以增强患者对ICB的反应。局灶性放射疗法（RT）至少部分通过诱导，增加了对ICB治疗的反应 I型干扰素（IFN-I）并将CDC1驱动到辐照的肿瘤中。我们以前已经表明CDC1是必不可少的用于治疗的小鼠的辐照和同步非辐照肿瘤的免疫介导的回归（脱离肿瘤）与RT和ICB。在接受RT和ICB治疗的转移性癌症患者中，也已经达到了潜在反应比预期的不太可靠，此类反应的决定因素尚不清楚。我们假设一个以前脱节反应的未开发障碍是通过CDC1对免疫原性肿瘤浸润有限，这排除在辐照肿瘤部位产生的效应T细胞无法拒绝非辐照肿瘤。而且，我们假设在辐照肿瘤中激活强大的IFN-I反应对于实现系统性至关重要天然杀伤（NK）细胞的激活，可以在非辐照的肿瘤中储存并促进CDC1的募集。这假设得到了一个强大的科学前提的支持，该前提是基于最近的文献和我们广泛的已发表和未发表的数据，包括血清IFNB后RT增加的事实是潜线的最佳预测因子用RT+抗CTLA4治疗的转移性肺癌患者的反应（NAT MED 2018）。检验这一假设三计划解决不同机械问题的独立但相关的目标。 AIM 1将调查角色 RNA的：DNA杂种，积聚在辐照癌细胞的胞质和小细胞外货物中它们产生的囊泡（SEV）在癌细胞和局部DC中通过CGA/STIN激活IFN-I途径。角色通过使用IFNAR1缺陷型NK细胞，将确认全身NK细胞激活中RT诱导的IFNB的IFNB。 AIM 2意志通过使用RAB27A缺乏的癌细胞，确定SEV对体内IFN-I激活的贡献。目标3意志直接解决了NK细胞在驱动CDC1浸润中的作用，在潜在的肿瘤中和对RT+ICB的潜线反应。在此外，肺癌血液中存在的NK细胞功能子集对RT+抗 - CTLA4将通过单细胞分析研究。拟议的研究结果将确定一种新的机制 RT局部IFN-I诱导激活NK细胞和CDC1之间的全身串扰，T细胞介导排斥潜线肿瘤。