Correction of dendritic cells defects in cancer

H. Lee Moffitt Cancer Ctr & Res Inst, Tampa FL

Investigators

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Abstract

DESCRIPTION (provided by applicant): Despite high promise the immunotherapeutic strategies that have been tested in clinical trials have not yet delivered tangible benefits to most patients. Numerous clinical trials have demonstrated successful generation of immune responses against tumor-specific antigens. However, these responses have not been associated with clinical responses in most patients. It has become increasingly clear that one of the major factors that limit the effectiveness of immunotherapy is the immunosuppressive tumor microenvironment, which prevents cytotoxic T cells (CTL) from recognizing and eliminating tumor. Parent grant is focused to understanding the mechanisms of T-cell defects induced by myeloid-derived suppressor cells (MDSC). In a course of implementation of the goals of the project we found that one of the major mechanisms of MDSC mediated T-cell tolerance was a posttranslational modification of TCR caused by increased production of reactive oxygen (ROS) and nitrogen (RNS) species by MDSC. In current revision we propose to expand the scope of the parent grant. Based on our new preliminary data we propose that effect of peroxynitrite and other ROS produced in tumor microenvironment by infiltrating myeloid cells or tumor cells is much broader than just effect on T cells. We suggest that peroxynitrite and ROS cause modification of MHC class I molecules expressed on tumor cells and/or tumor-specific peptides presented by those MHC class I molecules. This would make CTLs specific for tumor antigen derived peptides unable to recognize and eliminate tumor cells. Thus, even if cancer immunotherapy results in the generation of potent antigen-specific CTLs or if these CTLs are generated in vitro and then adoptively transferred to patients, post-translational modification of MHC class I would negate any possible antitumor effect. Since the level of myeloid cell infiltration and peroxynitrite production varies from patient to patient this may account for variable results of patients'treatment with adoptive transfer of T cells or vaccines. In the proposed study we plan to experimentally test this hypothesis. We will also test the possibility of reversing the effect of peroxynitrite by employing the novel compound RTA 402, which has been demonstrated to have a high level of activity in blocking reactive oxygen species and decreasing peroxynitrite production. We propose the following specific aims: Specific aim 1. To identify the mechanism of tumor escape associated with hyperproduction of reactive oxygen and nitrogen species in animal models of lung cancer. Specific aim 2. To determine in preclinical models of lung cancer the ability of novel therapeutic compounds to reverse the peroxynitrite-inducible tumor escape from cytotoxic T cells. PUBLIC HEALTH RELEVANCE: Proposed research will investigate novel mechanism of tumor escape associated with increased production of peroxynitrite in tumor tissues. We will test novel hypothesis that inability of cytotoxic T lymphocytes to recognize and eliminate tumor cells was caused in part by peroxynitrite inducible modifications of MHC class I and/or peptide epitopes on the surface of tumor cells. We will investigate the mechanism of this phenomenon and test several therapeutic approaches to eliminate this effect with goal to enhance the effect of cancer immunotherapy.