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.

概括 在女性中，乳腺癌（BC）是最常见的恶性肿瘤，也是第二大癌症原因 基础/三阴性 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，可用的治疗方法是一种明确的死亡特征。 受其同源配体 FasL 刺激时，允许细胞中的受体介导细胞凋亡诱导。 目前已证实 Fas 还具有多种非凋亡、肿瘤促进功能。 我们之前已经在多个基因组中证明了表达是 TNBC 的负面预后因素。 工程小鼠肿瘤模型具有组织特异性 Fas 缺失，癌细胞维持 Fas 表达 然而，如果没有 Fas，肿瘤就不会生长，但由于这些原因，这些敲除 (KO) 小鼠中仍然形成了一些肿瘤。 Cre 重组的“逃逸者”目前尚不清楚 Fas 的这种活动是细胞自主的还是细胞自主的。 TNBC 小鼠模型的新初步数据表明，肿瘤微环境所需的细胞。 肿瘤细胞表达的 Fas 发挥免疫抑制活性，促进骨髓源性细胞的募集 最近，抑制细胞（MDSC）导致自然杀伤（NK）细胞抑制肿瘤浸润。 我们发现，KPC2，一种新型 Fas 相互作用伙伴，可与 C 末端结合，并在未受刺激的情况下 TNBC 细胞隔离 NF-κB 亚基 p65 和 KPC1（一种降解 p50 的泛素连接酶） 我们发现，当 Fas 被消除时，p105 就会降解，从而改变 NF-κB 的平衡。 亚基从抑制性 p50/p50 同二聚体到转录活性 p50/p65 异二聚体。 释放多种促炎细胞因子的产生，调节多种细胞的募集 根据这些初步数据，我们发现 Fas 在 TNBC 中充当免疫细胞（包括 NK 细胞）。 NK 细胞的新免疫检查点可能通过重塑免疫景观来实现，即新的 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， 破坏这种相互作用会释放出抗肿瘤活性，可用于靶向 TNBC 细胞。 假设将在两个具体目标上进行研究： 具体目标 1：表征免疫抑制活性 三阴性乳腺癌中的 Fas 具体目标 2：确定 Fas 表达如何抑制 a 该项目的目标是表征 Fas 在促进 TNBC 方面的新活动。 该项目将增强我们对NK细胞的生长和转移及其免疫抑制功能。 关于复杂而关键的受体/配体信号对在癌症中的作用的知识，长期以来一直被人们所认识。 直到最近，FasL 的抑制（而不是其使用）才被认为是一种有价值的选择。 在 TNBC 中，我们现在的工作除了抑制 Fas 受体外，还针对癌症的临床治疗。 最后，Fas 的新型免疫抑制活性为结合提供了令人信服的理由。 使用常规检查点抑制剂抑制 Fas/FasL 治疗 TNBC。