Interactions between tumor cells and the microenvironment (TME) have a major impact on the biology of myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). This application is a continuation of our prior work wherein we characterized several aspects of TME in MM. A theme from our prior work is that transition of MGUS to MM is associated with several changes in TME, with loss of anti-tumor immunity and progressive inflammation. Herein we will pursue the link between properties of tumor cells and changes in TME. Based on our preliminary studies, we posit that secretion of wnt inhibitors by tumor cells and the recruitment of myeloid cells play a major role in the altered balance of immunity and inflammation.
In Aim 1, we will pursue the effect of wnt inhibitors on the regulation of host immune response.
In Aim 2, we will further characterize the crosstalk between myeloid cells and myeloma in the regulation of genomic instability. These studies may provide several targets to restore the dysregulation of immunity versus inflammation and restrict genomic instability in this cancer.
This work builds on our prior studies to better understand the changes in the properties of the tumor bed in myeloma. These studies may provide novel approaches to control tumor growth and achieve durable responses to therapy.
|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|
|Dhodapkar, Madhav V; Sexton, Rachael; Waheed, Sarah et al. (2014) Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood 123:78-85|
|Zhao, S; Choi, M; Heuck, C et al. (2014) Serial exome analysis of disease progression in premalignant gammopathies. Leukemia 28:1548-52|
|Sehgal, Kartik; Dhodapkar, Kavita M; Dhodapkar, Madhav V (2014) Targeting human dendritic cells in situ to improve vaccines. Immunol Lett 162:59-67|
|Dhodapkar, Madhav V (2013) Personalized immune-interception of cancer and the battle of two adaptive systems--when is the time right? Cancer Prev Res (Phila) 6:173-6|
|Richter, Joshua; Neparidze, Natalia; Zhang, Lin et al. (2013) Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma. Blood 121:423-30|
|Dhodapkar, Madhav V; Dhodapkar, Kavita M (2011) Vaccines targeting cancer stem cells: are they within reach? Cancer J 17:397-402|
|Dhodapkar, Madhav V; Richter, Joshua (2011) Harnessing natural killer T (NKT) cells in human myeloma: progress and challenges. Clin Immunol 140:160-6|
|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, Madhav V (2010) Immunity to stemness genes in human cancer. Curr Opin Immunol 22:245-50|
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