Cancer vaccines and new combinations of chemotherapy and immunotherapy are actively being tested in numerous clinical trials based on the exciting results of the pre-clinical animal studies. However, previous results of immunotherapy trials and the recent findings on the immune response in cancer, suggest that these trials will encounter a major barrier, namely the immune dysfunction present in cancer patients. This immune dysfunction is manifested in vivo by the loss of a delayed type hypersensitivity (DTH), and in vitro by a decreased cytotoxicity, a diminished production of cytokines and the inability to respond to antigenic stimuli. The basis of these changes is unclear, although alterations in T cell function and signal transduction as well as changes in dendritic cell maturation have been demonstrated recently. It is however logical to think that a successful immunotherapy must correct these immunological alterations. The alterations in T cell function appear to be related to changes in the expression of T cell signal transduction molecules. These include a decreased expression of T cell receptor chain (TCR), a diminished level of p56lck and Jak-3 kinases and an inability to translocate NFkB p65 to the nucleus. These changes are not only seen in cancer patients, but also in patients with other diseases characterized by immune dysfunction such as leprosy. Preliminary results from clinical trials suggest that patients responding to the treatment, or developing an immune response to tumor antigens, recover the normal expression of T cell signal transduction molecules. In contrast patients with progressive tumor growth show persistent alterations in signal transduction proteins. Therefore this application proposes to 1) determine the signal transduction alterations present in T cells of patients with cervical cancer prior to and after vaccination with human papilloma virus (HPV) peptide vaccine 2) test whether these alterations are paralleled by changes in in vivo and in vitro T cell functions, and 3) determine whether the re-expression of T cell signal transduction proteins correlates with a successful vaccination or the induction of a clinical anti-tumor response.
| Zea, Arnold H; Rodriguez, Paulo C; Culotta, Kirk S et al. (2004) L-Arginine modulates CD3zeta expression and T cell function in activated human T lymphocytes. Cell Immunol 232:21-31 |
| Bansal, Vishal; Rodriguez, Paulo; Wu, Guoyao et al. (2004) Citrulline can preserve proliferation and prevent the loss of CD3 zeta chain under conditions of low arginine. JPEN J Parenter Enteral Nutr 28:423-30 |
| Rodriguez, Paulo C; Quiceno, David G; Zabaleta, Jovanny et al. (2004) Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64:5839-49 |
| Rodriguez, Paulo C; Zea, Arnold H; DeSalvo, Joanna et al. (2003) L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol 171:1232-9 |
