Epha2 -/- NK Cell Therapy Against Malignant Pleural Mesothelioma
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive tumor of the pleura with extremely poor prognosis. The mean survival is less than a year after initial diagnosis. Prior exposure to asbestos is a major risk factor for MPM. Nearly 3,000 new MPM cases are diagnosed each year in the United States, and among these, 30% of cases are reported in the Veteran population. MPM is a complex disease and less responsive to current therapies. Therefore, novel therapeutic strategies are needed against MPM. Normally, natural killer (NK) cells serve as a natural cancer-defense, seeking out and destroying precancerous cells before they can do damage and establish in the body. Researchers recently have shown that in addition to cellular injury and inflammation, asbestos effectively turns off the body s natural killer cell response, leaving people more prone to developing cancer. Scientists believe that MPM may develop due to suppression of NK cell functions by the asbestos fibers. Since MPM is highly resistant to standard therapies, any research that sheds light on tumor cell death could help the doctors in their efforts to find effective treatments. NK cells play a critical role in host immunity against cancer. Recent evidence indicates that adoptive transfer of allogeneic NK cells plays a crucial role in the elimination of cancer cells. Allogeneic NK cells have shown substantial clinical benefit against leukemia, renal carcinoma, and melanoma. However, adoptive transfer of allogeneic NK cells attenuate MPM tumor growth is not known. Malignant cells evade NK cell attack by developing mechanisms depending upon the signals in the milieu. In MPM, NK cell activity is impaired, and the NK cells isolated from MPM patients showed decreased cytotoxicity due to altered expression of activating receptors indicating an immune-suppressive and tumorigenic effect. EphA2, a tyrosine receptor kinase, is overly expressed in MPM. In earlier studies we showed silencing EphA2 attenuated MPM tumor growth and we also noticed stunted MPM tumor growth in EphA2-/- mice. The mammary carcinoma tumor growth was also impaired in EphA2-/- mice. In addition, T cells from EphA2-/- mice showed efficient migration and increased cytotoxic effect against mammary cancer cells. However, it is not known if EphA2-/- NK cells evoke effective anti-tumor activity against MPM. Therefore, in this project experiments are designed to understand the efficacy and mechanisms of NK cell cytotoxicity against MPM. We hypothesized that MPM treatment with adoptive transfer of allogeneic EphA2-/- NK cells may attenuate tumor growth via induction of cytotoxic signals and apoptosis in a well-established and clinically relevant mouse model of MPM. We investigate our hypothesis in following two specific aims: Aim 1: To determine if adoptive transfer of allogeneic NK cells from tumor bearing EphA2-/- mice inhibit MPM tumor growth in Nude mice in vivo. Aim 2: To determine the functional repertoire and the mechanisms of cytotoxic activity of EphA2-/- NK cells against MPM in vitro. The studies proposed will not only clarify the role of NK cells from EphA2-/- mice but also provide the understanding of novel therapeutic insights for targeting MPM. Since we planned to utilize a well-established preclinical murine model of MPM to study the efficacy of EphA2-/- NK cells against MPM, the data generated will be highly significant. The findings from the project will help build knowledge necessary to develop potential and novel therapeutic strategies against MPM.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510523
Entities
People
- Nasreen Najmunnisa
Organizations
- United States Army
- University of Florida