Grant: $508,515 - National Institutes of Health - Sep. 17, 2009
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Award Description: Inability of host immune system to develop and/or maintain antitumor responses is one of the major factors responsible for tumor escape and low efficacy of cancer vaccines. A large number of different immune suppressive factors have been described to date. They include cytokines and soluble mediators, inhibitory receptors, regulatory T cells, tumor associates macrophages, inhibitory subsets of DCs and many others. However, despite the presence of all these factors tumor-bearing mice or cancer patients usually don’t dis-play significant systemic immunodeficiency1,2. At the same time, profound deficiency in T-cell function are routinely observed in tumor tissues (rev. in 3,4). It became increasingly clear that immune defects in tumor bearing hosts are compartmentalized. In tumor milieu a multitude of different factors associated with tumor cells and tumor stroma create potent immune suppressive environment. In contrast, the main component of the systemic immune defects is antigen-specific T-cell tolerance. Understanding the mechanisms of T-cell tolerance in cancer is critically important for the development of most effective therapeutic strategies. It has been previously shown that T-cell tolerance in cancer is caused not by tumor cells but by host antigen pre-senting cells. However, the exact nature of these cells and the mechanism of this effect remain unclear. In-tensive studies during recent years have provided evidence that myeloid-derived suppressor cells (MDSC) play a critical role in immune defects in cancer. MDSC induce antigen-specific T-cell suppression in vitro. Their elimination dramatically improved antitumor immune responses. Most recently in direct experiments in vivo MDSC were shown to cause CD8+ T-cell tolerance. We proposed that MDSC via hyper-production of peroxynitrite induce modification of TCR and CD8 molecules on the surface of antigen-specific T cells. This process requires close cell-cell contact and the presence of specific antigen. Nitrate modification of TCR and CD8 alters T-cell recognition of the specific antigens. This mechanism may explain the phe-nomenon of tumor-specific T-cell tolerance. 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 microenviron-ment 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 tu-mor 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 re-versing the effect of peroxynitrite by employing the novel compound RTA 402, which has been demon-strated 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 com-pounds to reverse the peroxynitrite-inducible tumor escape from cytotoxic T cells.
Project Description: This award was issued on 9/17/09 and, therefore, did not have any activities to report this quarter.
Jobs Summary: n/a (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 17, 2009. Help expand these official descriptions using the wiki below.