Adoptive immunotherapy is one strategy used to enhance immune responses in cancer patients. Treatments utilizing engineered T cells have the potential to offer long term protection, through memory, but are directed only towards cancer cells expressing the tumor antigen for which they were designed. This therapy is therefore limited by the possibility of tumor escape - a tumor can down regulate the antigen to which the immunotherapy is directed. An alternate cellular strategy in development utilizes natural killer (NK) cells. NK cells directly lyse cancer cells, and produce cytokines and chemokines that can activate other components of the immune system. Here, we propose to examine a third type of cellular therapy based on Natural killer T (NKT) cells. NKT cells can active both NK cells and classical T cells. Their dual function is ideal for cancer treatment, because NKT cell-based therapy offers the possibility of inducing an initial cytotoxic tumor response, and also activating the adaptive immune system to produce tumor-directed cytotoxic T cells (CTL) with long lived memory. We have developed a novel method to generate NKT cells from human adult stem cells. We hypothesize that these stem cell-derived NKT cells will exert potent anti-tumor responses. We will characterize our newly generated NKT cells by assessing their phenotype throughout development, and analyzing their function both in vitro and in vivo. The information gained in the proposed studies will serve to help understand and design NKT cell based immunotherapeutic approaches for the treatment of cancer.
Public Health Relevance Statement The incidence of lymphoma in the US is rising. Clinical studies have demonstrated that while immunotherapy can effectively treat lymphoma early, many patients relapse resulting in 20,000 US deaths each year. In this application, we propose an innovative method to generate natural killer T cells from adult stem cells and to assess their ability to enhance anti-tumor immune responses. This work is important because it could lead to the development of new therapeutic strategies for the treatment of lymphoma.
| Shissler, Susannah C; Webb, Tonya J (2018) The ins and outs of type I iNKT cell development. Mol Immunol 105:116-130 |
| Bates, Joshua P; Derakhshandeh, Roshanak; Jones, Laundette et al. (2018) Mechanisms of immune evasion in breast cancer. BMC Cancer 18:556 |
| Bollino, Dominique; Webb, Tonya J (2017) Chimeric antigen receptor-engineered natural killer and natural killer T cells for cancer immunotherapy. Transl Res 187:32-43 |
| Shissler, Susannah C; Bollino, Dominique R; Tiper, Irina V et al. (2016) Immunotherapeutic strategies targeting natural killer T cell responses in cancer. Immunogenetics 68:623-38 |
| Tiper, Irina V; East, James E; Subrahmanyam, Priyanka B et al. (2016) Sphingosine 1-phosphate signaling impacts lymphocyte migration, inflammation and infection. Pathog Dis 74: |
| Webb, Tonya J; Carey, Gregory B; East, James E et al. (2016) Alterations in cellular metabolism modulate CD1d-mediated NKT-cell responses. Pathog Dis 74: |
| Tiper, Irina V; Webb, Tonya J (2016) Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma. Cancer Immunol Immunother 65:1411-1421 |
| Tiper, Irina V; Webb, Tonya J (2016) Targeted attack: mechanisms by which ovarian cancers suppress the immune system. Transl Cancer Res 5:S1305-S1306 |
