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

• 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
• 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

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，肿瘤中存在传统的树突状细胞1型（cDC 1）， 免疫微环境（TME）是对免疫检查点阻断（ICB）疗法的应答所必需的。除了交叉- 将癌细胞衍生的抗原呈递给CD 8+和CD 4 + T细胞，cDC 1促进效应T细胞的肿瘤浸润， 并支持它们的生存和功能。因此，改善cDC 1向TME募集的干预措施可以增强 患者对ICB的反应。局部放射治疗（RT）增加了对ICB治疗的反应，至少部分是通过诱导 I型干扰素（IFN-I）和驱动cDC 1进入照射的肿瘤。我们之前已经证明，cDC 1是必不可少的， 用于免疫介导的经辐照和同步非辐照肿瘤消退（远位效应） RT和ICB。在接受RT和ICB治疗的转移性癌症患者中也实现了远位反应，但 可靠性低于预期，而且这种反应的决定因素仍不清楚。我们假设， 远端反应的未探索障碍是cDC 1对免疫原性较差的肿瘤的有限浸润，这 阻止在照射的肿瘤部位产生的效应T细胞排斥未照射的肿瘤。而且我们 假设在照射肿瘤中激活强IFN-1应答对于实现系统性 自然杀伤（NK）细胞的激活，可以归巢未照射的肿瘤并促进cDC 1的募集。这 这一假设得到了一个强有力的科学前提的支持，这一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RT后血清IFNb升高是异位妊娠的最佳预测因素， 接受RT+抗CTLA 4治疗的转移性肺癌患者的缓解（Nat Med 2018）。为了验证这一假设， 针对不同的机械问题，规划了独立但相关的目标。目标1将研究 RNA：DNA杂交体，其在辐射的癌细胞的胞质溶胶中和小的细胞外基质的货物中积累。 它们产生的小泡（sEV），在癌细胞和局部DC中通过cGAS/STING激活IFN-I途径。的作用 将通过使用IFNAR 1缺陷型NK细胞来确认RT诱导的IFNb在系统性NK细胞活化中的作用。目标2将 通过使用Rab 27 a缺陷型癌细胞确定sEV对RT诱导的IFN-I体内活化的贡献。目标3将 直接解决NK细胞在驱动远端肿瘤中的cDC 1浸润和对RT+ICB的远端应答中的作用。在 此外，在对RT+抗-IFN-γ有远位应答的肺癌患者的血液中存在NK细胞功能亚群。 将通过单细胞分析研究CTLA 4。拟议研究的结果将确定一种新的机制， 通过RT的局部IFN-1诱导激活NK细胞和cDC 1之间的系统性串扰，这是T细胞介导的免疫应答所必需的。 远位肿瘤的排斥反应。