My goal is to understand the adaptive and innate immune responses to glioma cells, and to identify ways to harness the immune system to resist these tumors in children. The prognosis for children with brain tumors remains poor with current modalities of treatment and brain tumors are now the leading cause of cancer related mortality and morbidity in children with solid tumors. Dendritic cells (DCs) are potent antigen presenting cells central to initiating and regulating both innate and adaptive immunity. They can process and present tumor antigens from dying tumor cells to elicit tumor specific killer T cells and DCs loaded with a-Galactosylceramide are able to stimulate Natural killer T (NKT) cells. My hypothesis is that harnessing both T and NKT cells is critical to optimal anti-glioma immunity. This application builds on two sets of findings that I have made in the lab. First that presentation of tumor antigens by the DCs can be enhanced by coating of the tumor cells with monoclonal antibodies. Second, that the NKT cells in glioma patients are functional and can be activated to mediate lysis of CD ld positive g lioma cells. Interestingly, CD ld is also overexpressed on tumor vessels, potentially allowing for these immune effectors to mediate anti-angiogenesis.
The specific aims of the proposed research plan are 1. To characterize the CDld restricted invariant NKT cell response in patients with glioma, 2) optimize presentation of tumor antigens from glioma cells by DCs and 3. To look for cooperation between T and NKT cell response in resisting glioma. The educational plan of this K08 includes laboratory experience in immunological and clinical research methods along with extensive didactic teaching through coursework, seminars and conferences. The proposed experiments will allow me to gain new information on innate and adaptive immunity to glioma, how to measure it, how to optimize antigen presentation, and to determine whether we can enhance anti-glioma immunity by simultaneous stimulation of the innate and adaptive immune system. The results of the above experiments will provide the baseline for the development of a novel immune based approaches for diagnosis and treatment in these children. Together with the educational plan, I should ultimately be able to lead an independent laboratory in this exciting field.
|Sehgal, Kartik; Ragheb, Ragy; Fahmy, Tarek M et al. (2014) Nanoparticle-mediated combinatorial targeting of multiple human dendritic cell (DC) subsets leads to enhanced T cell activation via IL-15-dependent DC crosstalk. J Immunol 193:2297-305|
|Guo, Xiuyang; Dhodapkar, Kavita M (2012) Central and overlapping role of Cathepsin B and inflammasome adaptor ASC in antigen presenting function of human dendritic cells. Hum Immunol 73:871-8|
|Dhodapkar, Kavita M; Feldman, Darren; Matthews, Phillip et al. (2010) Natural immunity to pluripotency antigen OCT4 in humans. Proc Natl Acad Sci U S A 107:8718-23|
|Dhodapkar, M V; Dhodapkar, K M; Palucka, A K (2008) Interactions of tumor cells with dendritic cells: balancing immunity and tolerance. Cell Death Differ 15:39-50|
|Dhodapkar, Kavita M; Barbuto, Scott; Matthews, Phillip et al. (2008) Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17-1 cells) enriched in the bone marrow of patients with myeloma. Blood 112:2878-85|
|Banerjee, Devi; Matthews, Phillip; Matayeva, Elyana et al. (2008) Enhanced T-cell responses to glioma cells coated with the anti-EGF receptor antibody and targeted to activating FcgammaRs on human dendritic cells. J Immunother 31:113-20|
|Dhodapkar, Madhav V; Dhodapkar, Kavita M; Li, Zihai (2008) Role of chaperones and FcgammaR in immunogenic death. Curr Opin Immunol 20:512-7|