Coaxing effector T cells into enhanced responses against cancer has proved challenging, in part because of a lack of understanding of how effector T cells are influenced by the tumor microenvironment. One approach to improve this understanding is to evaluate tumor responses in mice with altered signal transduction. Recent data has found that CD4+ T cells from mice deficient in diacylglycerol kinase 6 (dgk6) have increased production of IL2 and decreased sensitivity to inhibitory stimuli than their wild type counterparts. I wondered if CD8+ T cells from dgk6-deficient mice would show enhanced functional responses and whether dgk6-deficient mice were resistant to tumor development. My preliminary data indicate that dgk6-deficient CD8+ T cells produce more interferon-3 after TCR stimulation in vitro. Moreover, I have found that dgk6- deficient mice are resistant to tumors in both an EL4 subcutaneous injection model, and in the TRAMP model of spontaneous prostate cancer development. This grant proposes to extend these findings in two ways. First, the molecular underpinnings of TCR signaling in dgk6-deficient CD8+ T cells will be evaluated by assessing the phosphorylation state of intracellular signaling proteins after TCR stimulation, by determining their response to suboptimal peptide stimuli, and by evaluating their capacity to function under inhibitory conditions. Second, the tumor response of dgk6- deficient mice will be refined through the use of adoptive transfer experiments and by evaluating tumor phenotypes in mice with inducible deficiency of dgk6. This proposal describes a 5-year training program to develop an independent career as a laboratory-based academic physician scientist. Under the mentorship of Dr. Gary Koretzky, and utilizing the outstanding training environment in the Division of Hematology/Oncology at the University of Pennsylvania, this period of time will lead me to develop the skills I need to become an independent investigator evaluating the basic science behind T cell tumor responses. Ultimately, these studies have the potential to identify dgk6 as a novel target in the treatment of malignancy, one that could be coupled with existing immune-based therapeutic approaches. These studies will also add mechanistic insight into the process by which tumors thwart effective CD8+ T cell responses.
Current treatments of cancer have limited success and are generally toxic. We have found a new target for treating cancer, dgk-zeta, which awakens the immune system in mice, preventing cancer growth. This grant will figure out exactly how dgk-zeta works in a type of T cell known to attack cancer cells.
|Riese, Matthew J; Grewal, Jashanpreet; Das, Jayajit et al. (2011) Decreased diacylglycerol metabolism enhances ERK activation and augments CD8+ T cell functional responses. J Biol Chem 286:5254-65|