The cellular components of the BM milieu support multiple myeloma (MM) cell growth, survival, migration and drug resistance, both directly by cell-cell interactions as well as indirectly by production of soluble factors. A key component of this microenvironment is immune cells. During the previous granting period, we have demonstrated antigen specific anti-MM T and B cell responses in patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Although these responses can affect anti-MM cytotoxicity in vitro, they fail to impede disease progression. While the mechanisms governing tumor-induced immune dysfunction in MM patients are unknown, our preliminary data suggests that tumor cells can inhibit the development of an effective anti-MM immune response. Our preliminary data suggests a number of mechanisms mediating this immune inhibition including: induction of dysfunctional T regulatory cells;ineffective antigen presentation;soluble MICA induced suppression of NKG2D function, and production of excessive pro-inflammatory cytokines associated with NKG2D and TH17 pathways. Based upon these data, we hypothesize that the BM microenvironment modulates the immune responses towards NKG2D dysfunction and TH17 pathways to support tumor progression and inhibit the development of anti-MM immune responses. Our goal in Project 2 is to identify and target cellular and soluble factors modulating autologous anti-MM responses to develop effective strategies tageting these pathways to improve immune responses and inhibit myeloma cell growth. To achieve this goal, we propose the following Specific Aims: to elucidate the role of the NKG2D pathway in MM pathogenesis (Specific Aim 1);to evaluate the role of TH17 pathway and associated pro-inflammatory cytokines in promoting immune dysfunction and tumour growth in MM (Specific Aim 2);to evaluate the role of novel therapies targeting NKG2D and TH17 pathway in vitro and in vivo using animal models as a prelude to future phase I/II clinical trials (Specific Aim 3). These studies will provide the framework to improve immune function and to achieve anti-tumor responses in myeloma.
Our goal is to identify and target cellular and soluble factors modulating autologous anti-MM responses to develop effective strategies targeting these pathways to improve immune responses and inhibit myeloma cell growth.
|Tai, Yu-Tzu; Lin, Liang; Xing, Lijie et al. (2018) APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: therapeutic implications. Leukemia :|
|Bae, J; Hideshima, T; Zhang, G L et al. (2018) Identification and characterization of HLA-A24-specific XBP1, CD138 (Syndecan-1) and CS1 (SLAMF7) peptides inducing antigens-specific memory cytotoxic T lymphocytes targeting multiple myeloma. Leukemia 32:752-764|
|Pyzer, Athalia Rachel; Stroopinsky, Dina; Rajabi, Hasan et al. (2017) MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia. Blood 129:1791-1801|
|Cholujova, Danka; Bujnakova, Zdenka; Dutkova, Erika et al. (2017) Realgar nanoparticles versus ATO arsenic compounds induce in vitro and in vivo activity against multiple myeloma. Br J Haematol 179:756-771|
|Yin, Li; Tagde, Ashujit; Gali, Reddy et al. (2017) MUC1-C is a target in lenalidomide resistant multiple myeloma. Br J Haematol 178:914-926|
|Harada, T; Ohguchi, H; Grondin, Y et al. (2017) HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications. Leukemia 31:2670-2677|
|Hideshima, Teru; Cottini, Francesca; Nozawa, Yoshihisa et al. (2017) p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma. Blood 129:1308-1319|
|Ohguchi, H; Harada, T; Sagawa, M et al. (2017) KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival. Leukemia 31:2661-2669|
|Feng, Xiaoyan; Zhang, Li; Acharya, Chirag et al. (2017) Targeting CD38 Suppresses Induction and Function of T Regulatory Cells to Mitigate Immunosuppression in Multiple Myeloma. Clin Cancer Res 23:4290-4300|
|Bar-Natan, Michal; Stroopinsky, Dina; Luptakova, Katarina et al. (2017) Bone marrow stroma protects myeloma cells from cytotoxic damage via induction of the oncoprotein MUC1. Br J Haematol 176:929-938|
Showing the most recent 10 out of 270 publications