Human memory T cells present in ovarian tumor ascites fluids fail to respond to stimulation via the T cell receptor (TCR). This immunosuppression is manifest by decreases in NF-?B and NFAT activation, IFN-? production, and cell proliferation in response to stimulation via the T cell receptor (TCR). The non-responsiveness of the tumor-associated T cells (TAT) is quickly reversed when the cells are assayed after the removal of the tumor ascites fluid. The anergy of the TAT is easily re-established by the addition of cell free tumor ascites fluid in a dose dependent fashion. New preliminary data have established that two polar lipids phosphatidylserine (PS) and GD3 ganglioside (GD3), isolated from the ascites fluids, induce a TCR signaling arrest at or just proximal to PLC? in the TAT. Our long term goals are (1) to test the hypothesis that lipids present within human ovarian tumor microenvironments contribute to the anergy and to the failure of TAT to control tumor progression, and (2) that by blocking the immunosuppressive activity of the polar lipids T cells will become re-activated and mediate tumor killing in situ. Ai 1 focuses on whether the tumor ascites fluid, (or the two immunosuppressive polar lipids present in the ascites fluid), act directly on the T cells to induce the TCR signaling arrest or whether ths arrest is mediated indirectly by cells that bind to and are activated by the polar lipids. This firt aim will provide an initial rationale for the design of protocols to eliminate or functionally bloc the immunosuppressive lipids and/or lipid binding cells. We predict and will test in Aim 2 that blocking the lipid immunomodulatory effects will reverse the anergy of T cells present within an ovarian tumor microenvironment, prevent the induction of the TCR signaling arrest of functional T cells that enter the tumor, and will result in a T cell killing of tumor cells in the xenograft.
his aim i s dependent upon a novel xenograft model designed by the PI that has made it possible for the first time to quantify and monitor intratumoral T cell function and to quantify changes in tumor cell numbers. In the final aim structure/function studies of the two polar lipids (PS and GD3) isolated from the tumor ascites fluids are proposed. These studies are expected to provide further insights into the molecular mechanisms of the lipid-induced TCR signaling arrest, and to lead to the design of novel methods that target and block specific molecular structures that are found to be required for each molecule's inhibitory function. The success of our proposed studies is enhanced by the diverse expertise (including immunology, tumor cell biology, lipid biochemistry, genetics, animal modeling, membrane biophysics and clinical cancer immunotherapy) present within our collaborative research team that has been assembled by the PI.
Soluble factors present in tumors inhibit patients'immune responses to their tumor. By identifying the inhibitory factors and determining their mechanisms of action, we will attempt to block or reverse the inhibition of the tumor specific immune responses. The restoration of these responses is expected to result in the specific killing and eradication of the tumor.
|Kelleher Jr, Raymond J; Balu-Iyer, Sathy; Loyall, Jenni et al. (2015) Extracellular Vesicles Present in Human Ovarian Tumor Microenvironments Induce a Phosphatidylserine-Dependent Arrest in the T-cell Signaling Cascade. Cancer Immunol Res 3:1269-78|
|Fathallah, Anas M; Bankert, Richard B; Balu-Iyer, Sathy V (2013) Immunogenicity of subcutaneously administered therapeutic proteins--a mechanistic perspective. AAPS J 15:897-900|
|Gaitonde, Puneet; Ramakrishnan, Radha; Chin, Jamie et al. (2013) Exposure to factor VIII protein in the presence of phosphatidylserine induces hypo-responsiveness toward factor VIII challenge in hemophilia A mice. J Biol Chem 288:17051-6|
|Simpson-Abelson, Michelle R; Loyall, Jenni L; Lehman, Heather K et al. (2013) Human ovarian tumor ascites fluids rapidly and reversibly inhibit T cell receptor-induced NF-ÎºB and NFAT signaling in tumor-associated T cells. Cancer Immun 13:14|
|Yokota, Sandra J; Facciponte, John G; Kelleher Jr, Raymond J et al. (2013) Changes in ovarian tumor cell number, tumor vasculature, and T cell function monitored in vivo using a novel xenograft model. Cancer Immun 13:11|
|Bernstein, Joel M; Lehman, Heather; Lis, Maciej et al. (2012) Humanized mouse model used to monitor MUC gene expression in nasal polyps and to preclinically evaluate the efficacy of montelukast in reducing mucus production. Ann Otol Rhinol Laryngol 121:307-16|
|Lehman, Heather K; Simpson-Abelson, Michelle R; Conway Jr, Thomas F et al. (2012) Memory T cells in the chronic inflammatory microenvironment of nasal polyposis are hyporesponsive to signaling through the T cell receptor. J Assoc Res Otolaryngol 13:423-35|
|Bankert, Richard B; Balu-Iyer, Sathy V; Odunsi, Kunle et al. (2011) Humanized mouse model of ovarian cancer recapitulates patient solid tumor progression, ascites formation, and metastasis. PLoS One 6:e24420|
|Barnas, Jennifer L; Simpson-Abelson, Michelle R; Brooks, Stephen P et al. (2010) Reciprocal functional modulation of the activation of T lymphocytes and fibroblasts derived from human solid tumors. J Immunol 185:2681-92|
|Simpson-Abelson, Michelle R; Purohit, Vivek S; Pang, Wing Man et al. (2009) IL-12 delivered intratumorally by multilamellar liposomes reactivates memory T cells in human tumor microenvironments. Clin Immunol 132:71-82|
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