Immune Escape in Human Cancer: Mechanisms and Therapeutic Implications

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DESCRIPTION (provided by applicant): The goal of this PPG is to explore one of the major unsolved problems of modern tumor immunology, namely, the fate of immune cells in the tumor microenvironment. The working hypothesis is that in the patients with cancer, the immune cells are unable to effectively mediate anti-tumor activities, because human tumor cells can escape from the immune response and/or actively interfere with the differentiation, function and/or survival of immune effector cells. The failure of immunotherapy, including anti-tumor vaccines, to control tumor growth probably results from tumor-mediated dysfunction of the immune system and/or from successful strategies evolved by tumor cells to avoid immune detection. These hypotheses are solidly based on our preliminary data documenting dysfunction, Th2 deviation and spontaneous apoptosis of circulating CD8+ T cells; differentiation defects in dendritic cells (DC); and aberrations in the antigen processing machinery (APM) and antigen presentation by tumor cells. In four projects supported by four cores, this PPG will attempt to dissect mechanisms responsible for these abnormalities in anti-tumor immune responses. An improved understanding of these mechanisms is essential for the development of novel therapeutic strategies designed to protect tumor-specific effector T cells from apoptosis and restore balanced Th1/Th2 responses, adequate polarization and functions of DC as well as improved presentation of HLA-class l-tumor peptide complexes on the tumor cell surface. Cytokines and their impact on lymphocyte survival and tumor escape will be evaluated in vitro and in vivo, as part of the proposed clinical trials. In Project 1, spontaneous apoptosis of circulating tumor-specific CD8+ T cells will be investigated in patients with HNC or melanoma. Project 2 will explore molecular and functional consequences of immune deviation in tumor-antigen specific T helper cells in patients with renal cell cancer. In Project 3, new scFv probes for detection and quantitation of HLA-class I-tumor-peptide complexes will be developed and, together with antibodies to APM components, used for studies of mechanisms that contribute to tumor escape in patients with HNC. Clinical significance of APM defects and their repair upon therapy with IFN-y will be assessed. To accomplish these objectives, the PPG brings together basic and clinical investigators experienced in cancer immunology/immunotherapy. The overall goal is to prevent tumor cell escape and thereby improve effectiveness of anti-tumor immunotherapies.