This mentored research program is designed to develop the candidate's cognitive, technical, and interpretive skills to a sufficient degree that he will become an independent investigator. This will be done through hands-on experience in the laboratory, additional course work, manuscript and grant preparation, presentations at relevant national meetings, and interactions with other basic scientists. Through the additional training he receives from his mentor, while conducting his own original research as outlined in this proposal, the candidate hopes to transition his line of investigation smoothly to funding at the R01 level. ? ? Central to the concept of immunotherapy is the notion that cancer cells have antigens that the immune system may recognize as foreign and subsequently destroy. T cells of the adaptive immune system would seem to be ideal for this task, but through systems employing model tumor antigens it is becoming apparent that T cells may actually be down-regulated or rendered tolerant after encountering tumor antigens. This process appears to be mediated by professional antigen-presenting cells (APCs) and to occur in much the same way that T cells are naturally rendered tolerant to normal antigens expressed in peripheral tissues of the body. For this reason most current vaccination strategies are now focusing on up-regulating the APC or creating a local milieu that leads to priming rather than tolerance. ? ? Using a model system of spontaneously arising osteosarcoma in which transgenic mice express the T antigen of SV40 under an alpha-amylase promoter, the candidate is able to track CD8+ T cells that recognize a distinct foreign epitope of the T antigen and observe them to be rendered tolerant in response to the tumor antigen. He now proposes to 1) further investigate the mechanism of this immunologic tolerance, 2) to change this tolerance to priming by up-regulating the APC, and 3) to study the differences in tumor antigen presentation that lead to tolerance versus priming. ? ?
| Avella, Diego M; Li, Guangfu; Schell, Todd D et al. (2012) Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model. Hepatology 55:141-52 |
| Avella, Diego M; Kimchi, Eric T; Donahue, Renee N et al. (2010) The opioid growth factor-opioid growth factor receptor axis regulates cell proliferation of human hepatocellular cancer. Am J Physiol Regul Integr Comp Physiol 298:R459-66 |
| Ryan, Christina M; Staveley-O'Carroll, Kevin; Schell, Todd D (2008) Combined anti-CD40 conditioning and well-timed immunization prolongs CD8+ T cell accumulation and control of established brain tumors. J Immunother 31:906-20 |
