Changes of CD4+ Lymphocyte Profile in Patients with Renal Cell Carcinoma and its

肾细胞癌及其相关疾病患者CD4淋巴细胞谱的变化

• 批准号: 8121426
• 负责人: Walter J. Storkus
• 金额: $ 25.82万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8121426
• 关键词: Antibodies; Antigens; Apoptosis; Apoptotic; Biological Assay; Blood; CD4 Positive T Lymphocytes; Cell Death; Clinical Trials; Clinical Trials Design; Disease; Environment; Epitopes; Equilibrium; Exhibits; Family member; Flow Cytometry; Frequencies; Functional disorder; HLA-DR4 Antigen; ITGAM gene; ITGAX gene; Immune; Immune System Diseases; Immunity; Immunosuppressive Agents; In Situ; In Vitro; Ligands; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediator of activation protein; Methods; Monitor; Nature; No Evidence of Disease; Operative Surgical Procedures; Organ; Patients; Peptide/MHC Complex; Peptides; Phase; Phenotype; Physiologic pulse; Population; Production; Relative (related person); Renal Cell Carcinoma; Residual Tumors; Safety; Serum-Free Culture Media; Staging; T cell response; T-Lymphocyte; T-bet protein; Testing; Time; Translating; Tumor Antigens; Tumor Specific Peptide; Tumor-Derived; Vaccination; Vaccines; Viral; advanced disease; annexin A5; base; chemokine; cytokine; design; expectation; flu; melanoma; migration; novel; peripheral blood; programs; response; tumor

We have previously observed a strong bias in the functional polarization of tumor-specific CD4+ T cell responses in the peripheral blood of patients with advanced stage renal cell carcinoma (RCC), cervical cancer or melanoma. Notably, patients with active disseminated disease were typically characterized by predominant Th2- or T regulatory-type immunity to tumor antigen-derived Th epitopes, while those patients successfully treated and exhibiting no evidence of disease (NED) at the time of analysis, displayed principally Th1-type immune reactivity to these same epitopes. Virtually all patients retained Th1-type immunity to viral (EBV, Flu) Th epitopes, regardless of disease stage, supporting the tumor-specific nature of immune deviation in the CD4+ T cell compartment of these cancer-bearing patients. In the current proposal, we will determine mechanism(s) underlying Th immune deviation in patients with RCC, resolve means by which to correct such deficiencies in vitro and then translate corrective therapies into a phase l/ll clinical trial designed to treat patients with advanced stage RCC. Specifically, we will: Aim 1. Test the hypothesis that tumor-specific Th1-type immune deviation in patients with advanced stage RCC involves tumor-induced alterations in the balance of DC functional subsets or DC-expressed costimulatory molecues. Aim 2. Test the hypothesis that tumor-specific Th1-type immune dysfunction in RCC patients with active disease involves the preferential apoptosis of Th1-type, but not Th2- or T regulatory-type CD4+ T cells. Aim 3. Test the hypothesis that aDC1-based vaccines can correct dysfunctional, antigen-specific Type-1 immunity in vitro. Aim 4. Test the hypothesis that aDC1/tumor peptide-based vaccination of RCC patients with advanced disease will correct dysfunctional anti-RCC Type-1 CD4+ T cell responses in a phase l/ll clinical trial.

我们之前已经观察到肿瘤特异性CD4+ T细胞的功能极化有很强的偏倚