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.

总结