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

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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.