Role of antigen-specific CD4+ T cells in anti-tumor immune response in neoplastic patients Animal models have shown a critical role for CD4+ T cells in the anti-tumor response. CD4+ T cells provide help for induction and maintenance of anti-tumor CD8+ T cells, and exert effector functions both indirectly via cytokine release and directly on MHC class II molecule expressing tumor cells. However, along with productive pro-inflammatory responses CD4+ T cells may also exert regulatory functions.
The adaptive effector CD4+ T cell mediated immune response is highly heterogeneous, based on the development of distinct subsets that are characterized by different profiles of cytokine production. Th1 cells produce IFN-gamma and are mainly devoted to protection against intracellular microbes. Th2 cells produce IL-4, IL-5 and IL-13 and are involved in the protection against gastrointestinal nematodes, but are responsible for allergic disorders. Th0 cells produce both Th1 and Th2 cytokines. More recently a new subset has been identified: Th17 cells produce IL-17 and IFN-gamma and have been associated to autoimmunity. CD4+ T cell subsets endowed with regulatory function are Th3 and Tr1 produce TGF-beta and/or IL-10.
In order to investigate the existence and the role of tumor antigen specific CD4+ T cells in the human system, we developed a reverse immunology approach. Known tumor associated antigen are screened by bioinformatics for epitopes predicted to form MHC class II binders. Peptides corresponding to the predicted epitopes are used to study in vitro the quantity and the quality of tumor antigen epitope specific CD4+ T cells in normal donors and neoplastic patients. The pathologies we are interested in are: melanoma, pancreatic cancer and cervical cancer. We were able to show the presence of MAGE-3 specific CD4+ T cells in advanced melanoma patients, caercinoembryonic specific CD4+ T cells in pancreatic cancer patients and human papilloma virus specific CD4+ T cells in patients with cervical lesions. We found that production of IFN-gamma by tumor antigen specific CD4+ T cells correlates with a favorable clinical outcome, while Th2 cytokine production (mainly IL-5 and IL-13) is associated with severe or advanced neoplastic disease. The observed Th2 skew is tumor antigen specific because in the same patients the repertoire of anti-viral CD4+ T cells is preserved and of Th1 type. Studies are in progress to identify tumor related factor(s) and mechanisms leading to the Th2 skew observed in advanced neoplastic patients. Moreover, phenotypic characteristics and effector functions of tumor antigen specific CD4+ T cells are being tested in clones obtained by limiting dilution from the patients.
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