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: 10514907
• 负责人: Marcus E. Peter
• 金额: $ 47.53万
• 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/10514907
• 关键词: Antitumor Response; Apoptosis; Binding; Binding Proteins; Biochemical; Biological Assay; 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; Knock-in; 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; Woman; Work; base; cancer cell; cancer subtypes; cancer therapy; crosslink; cytokine; design; immune activation; immune checkpoint; improved; in vivo; inhibitor; malignant breast neoplasm; molecular subtypes; mouse model; neoplastic cell; novel; p65; peptidomimetics; 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.

摘要 在女性中，乳腺癌是最常见的恶性肿瘤，也是第二大致癌原因。 死亡。基础/三重阴性BC(TNBC)患者的临床结果最差，没有针对性 与其他分子亚型相比，可用的治疗方法。Fas/CD95是一种典型的死亡 一种受体，在其同源配体FasL的刺激下，在允许细胞中介导诱导细胞凋亡。它 现在已经确定Fas还具有多种非凋亡性、促肿瘤功能。高Fas 表达是TNBC的一个负面预后因素。我们之前已经在多个基因上证明了 组织特异性Fas缺失使癌细胞维持Fas表达的工程化小鼠肿瘤模型 没有Fas，肿瘤就不会生长。然而，一些肿瘤仍然在这些基因敲除(KO)小鼠中形成，这是由于 从CRE重组中脱颖而出。目前尚不清楚Fas的这种活动是细胞自主的还是 肿瘤微环境所需的细胞。关于TNBC小鼠模型的新的初步数据现在表明 表达Fas的肿瘤细胞具有促进髓系细胞集结的免疫抑制活性 抑制细胞(MDSCs)通过自然杀伤(NK)细胞抑制肿瘤的侵袭。最近一次 我们发现，KPC2是一种新的Fas相互作用伙伴，它与C端结合，并在未受刺激的情况下 TnBC细胞同时隔离NF-κB亚单位p65和KPC1，后者是一种降解p50的泛素连接酶 前体p105。我们发现，当Fas被消除时，P105被降解，改变了NF-κB的平衡 亚基从抑制性p50/p50同源二聚体到转录活性p50/p65异源二聚体。这反过来又会导致 释放一些促炎细胞因子的产生，这些细胞因子调节许多 包括NK细胞在内的免疫细胞。根据这些初步数据，我们假设在TNBC中，Fas扮演着一个 NK细胞的新免疫检查点可能通过重塑免疫格局，即一种新的Fas结合 KPC2周围的蛋白质复合体负责Fas的这种免疫抑制活性，最后， 破坏这种相互作用会释放一种可用于靶向TNBC细胞的抗肿瘤活性。这些 假说将在两个特定目标下进行研究：特定目标1：表征免疫抑制活性 Fas在三阴性乳腺癌中的表达特定目标2：确定Fas表达如何抑制 促炎计划。该项目的目标是描述金融服务局在促进跨国公司方面的新活动 其生长、转移及其对NK细胞的免疫抑制作用。该项目将增加我们的 关于复杂和关键的受体/配体信号对在癌症中的作用的认识 被误解了。直到最近，抑制FasL(而不是使用FasL)才被认为是一种有价值的选择 在临床上治疗癌症。在TNBC中，我们的工作现在指向抑制Fas受体，除了 它的配体。最后，Fas新的免疫抑制活性提供了一个令人信服的理由来结合 用常规检查点抑制剂抑制Fas/FasL治疗TNBC