Novel immune suppressive activities of Fas/CD95 in triple negative breast cancer

Fas/CD95 在三阴性乳腺癌中的新型免疫抑制活性

• 批准号: 10661817
• 负责人: Marcus E. Peter
• 金额: $ 45.11万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-07 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661817
• 关键词: Antitumor Response; Binding; Binding Proteins; Biochemical; Biological Assay; Breast Cancer Cell; C-terminal; CD95 Antigens; Cancer Etiology; Cells; Cessation of life; Clinic; Clinical; Complement; Complex; Data; Equilibrium; Fas Signaling Pathway; Genetic Recombination; Genetic Transcription; Genetically Engineered Mouse; Goals; Growth; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunosuppression; Immunotherapy; Implant; In Vitro; Induction of Apoptosis; Infiltration; Inflammatory; Killer Cells; Knock-out; Knockout Mice; Knowledge; Ligands; Lymphocytic Infiltrate; Malignant Neoplasms; Mediating; Modeling; Molecular; Mouse Cell Line; Mouse Strains; Mus; Myeloid-derived suppressor cells; NF-Kappa B p65; NF-kappa B; NMR Spectroscopy; Natural Killer Cells; Nature; Neoplasm Metastasis; Outcome; Patients; Production; Prognosis; Prognostic Factor; Public Health; Role; Signal Transduction; TNFRSF5 gene; TNFRSF6 gene; Testing; Tissues; Tumor Promotion; Woman; Work; cancer cell; cancer subtypes; cancer therapy; crosslink; cytokine; derepression; design; immune activation; immune checkpoint; improved; in vivo; inhibitor; malignant breast neoplasm; molecular subtypes; mouse model; neoplastic cell; novel; p65; peptidomimetics; permissiveness; programs; protein complex; receptor; recruit; screening; single-cell RNA sequencing; small molecule libraries; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; ubiquitin ligase

Summary Among women, breast cancer (BC) is the most common malignancy, and the second leading cause of cancer death. Patients with basal/triple negative BC (TNBC) have the poorest clinical outcome with no targeted therapies available when compared to other molecular subtypes. Fas/CD95 is a well characterized death receptor that in permissive cells mediates induction of apoptosis when stimulated by its cognate ligand, FasL. It is now well established that Fas also has multiple nonapoptotic, tumor promoting functions. High Fas expression is a negative prognostic factor for TNBC. We have previously demonstrated in multiple genetically engineered mouse tumor models with tissue specific deletion of Fas that cancer cells maintain Fas expression and without Fas tumors do not grow. However, some tumors still formed in these knock-out (KO) mice due to ‘escapers’ from Cre recombination. It remained unclear whether this activity of Fas was cell autonomous or required cells of the tumor microenvironment. New preliminary data on a mouse model of TNBC now suggest that tumor cell expressed Fas exerts an immune suppressive activity promoting recruitment of myeloid derived suppressor cells (MDSCs) resulting in inhibition of tumor infiltration by natural killer (NK) cells. Most recently we discovered, KPC2, a novel Fas interaction partner that binds to the C-terminal end and in unstimulated TNBC cells sequesters both the NF-κB subunit p65 and KPC1, a ubiquitin ligase that degrades the p50 precursor p105. We found that when Fas is eliminated p105 gets degraded shifting the balance of NF-κB subunits from repressive p50/p50 homodimers to transcriptionally active p50/p65 heterodimers. That in turn unleashes production of a number of proinflammatory cytokines that regulate the recruitment of a number of immune cells including NK cells. Based on these preliminary data we hypothesize that in TNBC Fas acts as a novel immune check point for NK cells likely by remodeling the immune landscape, that a novel Fas bound protein complex around KPC2 is responsible for this immune suppressive activity of Fas and finally, that disrupting this interaction unleashes an antitumor activity that can be used to target TNBC cells. These hypotheses will be studied in two specific aims: Specific Aim 1: Characterize immune suppressive activities of Fas in triple negative breast cancer. Specific Aim 2: To determine how Fas expression suppresses a proinflammatory program. The goal of this project is to characterize novel activities of Fas in promoting TNBC growth and metastasis as well as its immune suppressive function on NK cells. The project will increase our knowledge on the role of a complex and critical receptor/ligand signaling pair in cancer that has long been misunderstood. Only recently has inhibition of FasL (and not its use) been recognized as a valuable option for the treatment of cancer in the clinic. In TNBC our work now points at inhibiting the Fas receptor in addition to its ligand. Finally, the novel immune suppressive activity of Fas provides a compelling rationale to combine Fas/FasL inhibition with conventional checkpoint inhibitors for the treatment of TNBC.

概括 在妇女中，乳腺癌（BC）是最常见的恶性肿瘤，也是癌症的第二大原因 死亡。基本/三重阴性BC（TNBC）患者的临床结局最差，没有针对性 与其他分子亚型相比，可用的疗法。 FAS/CD95是一个表征良好的死亡 当允许细胞中，当其同源配体FASL刺激时，受体会介导凋亡的诱导。它 现在已经很好地确定，FAS还具有多个非凋亡的肿瘤促进功能。高FAS 表达是TNBC的负预后因素。我们以前曾在多个一般中演示 具有组织特异性缺失的FAS的工程小鼠肿瘤模型，癌细胞保持FAS表达 并且没有FAS肿瘤不会生长。但是，由于 从CRE重组中“逃脱者”。目前尚不清楚FAS的这种活性是细胞自主还是 肿瘤微环境所需的细胞。现在建议的TNBC鼠标模型上的新初步数据 该肿瘤细胞表达Fas导出了髓样衍生的免疫抑制活性促进募集 抑制细胞（MDSC）导致自然杀伤（NK）细胞抑制肿瘤浸润。最近 我们发现，KPC2是一种新型的FAS相互作用伴侣，与C末端结合，并在未刺激中结合 TNBC细胞隔离NF-κB亚基P65和KPC1，这是一种泛素连接酶，可降解P50 前体P105。我们发现，当消除FAS时，P105会降解以移动NF-κB的平衡 从反射P50/P50同型二聚体到转录活性P50/P65异二聚体的亚基。反过来 释放许多调节许多募集的促炎细胞因子的产生 免疫细胞包括NK细胞。基于这些初步数据，我们假设TNBC FAS充当 NK细胞的新型免疫检查点可能是通过重塑免疫景观而进行的，该景观是一种新型的Fas结合 KPC2周围的蛋白质复合物负责FAS的这种免疫抑制活性，最后是 破坏这种相互作用会释放可用于靶向TNBC细胞的抗肿瘤活性。这些 假设将以两个特定目的进行研究：具体目标1：表征的免疫抑制活动 FAS三重阴性乳腺癌。特定目的2：确定FAS表达如何抑制A 促进计划。该项目的目的是表征FAS在促进TNBC中的新型活动 生长和转移以及其在NK细胞上的免疫抑制功能。该项目将增加我们的 关于复杂而关键的接收器/配体信号对在癌症中的作用的知识 误解。直到最近才抑制FASL（而不是其使用）被认为是有价值的选择 诊所的癌症治疗。在TNBC中，我们的工作现在指向抑制FAS受体。 它的配体。最后，FAS的新型免疫抑制活性提供了令人信服的理由 通过常规检查点抑制剂进行TNBC治疗的FAS/FASL抑制。