B-cell lymphomas, being tumors derived from cells with intrinsic antigen-presenting cell capabilities (B- lymphocytes) can efficiently process and present antigens to antigen-specific T-cell in vitro. However, the in vivo growth of these malignancies usually results in the induction of T-cell tolerance rather than T-cell activation. Bone marrow-derived antigen-presenting cells (APCs) play a dominant role in the induction of this state of T-cell unresponsiveness. Importantly, we have previously demonstrated that in vivo disruption of these APC-mediated tolerogenic mechanisms unleashed the intrinsic antigen-presenting abilities of malignant B-cells resulting in T-cell activation and development of anti-lymphoma immunity. Therefore, generation of an effective anti-lymphoma immunity has two critical requirements: (1) Conversion of BM-derived APCs from a non- inflammatory/tolerogenic status into an inflammatory/activating one, and (2) Augmentation of the antigen- presenting cell function of the malignant B-cell. Both requirements we have found, can be fulfilled by manipulation of intracellular pathways involved in regulation of inflammatory responses. In this proposal we will test the hypothesis that Stat3 inhibition and/or disruption of specific histone deacetylases (HDACs), by abrogating anti-inflammatory mechanisms and/or promoting inflammatory pathways in the malignant B-cells and/or APCs would trigger an effective and long-lasting immunity against Mantle Cell Lymphoma(MCL), and aggressive and incurable subtype of Non-Hodgkin's lymphomas. To achieve our goals, we will use a combination of specific molecular tools and novel pharmacologic inhibitors to gain mechanistic insights into the role of Stat3 signaling and HDAC6/HDAC11 in regulating inflammatory responses in B-cell lymphomas. In vitro and in vivo studies in mouse models (Aims 1 and 2) and in human MCL cells (Aim 3) are proposed within this comprehensive, mechanistically-oriented and translational project that we believe would result in innovative immunotherapeutic strategies for B-cell malignancies.

Public Health Relevance

Mantle cell lymphoma (MCL) is a cancer that arises in lymphoid organs and progresses in the same compartment where important cells of the immune system (T-lymphocytes) are also located, indicating that MCL has developed mechanism(s) to avoid immune attack. Recently, we have identified two intracellular pathways (Stat3 signaling and Histone deacetylases) that impose a significant barrier to our efforts to augment anti-tumor immune responses. The goal of this application is to better understand these barriers and design therapeutic interventions to overcome them and elicit sustained immunity against MCL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134807-05
Application #
8628072
Study Section
Special Emphasis Panel (ZRG1-OTC-W (03))
Program Officer
Muszynski, Karen
Project Start
2010-06-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$437,284
Indirect Cost
$143,648
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Cheng, Fengdong; Lienlaf, Maritza; Perez-Villarroel, Patricio et al. (2014) Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells. Mol Immunol 60:44-53
Beltran, Brady E; Quiñones, Pilar; Morales, Domingo et al. (2013) Follicular lymphoma with leukemic phase at diagnosis: a series of seven cases and review of the literature. Leuk Res 37:1116-9
Zhao, X; Lwin, T; Zhang, X et al. (2013) Disruption of the MYC-miRNA-EZH2 loop to suppress aggressive B-cell lymphoma survival and clonogenicity. Leukemia 27:2341-50
Zhang, Xinwei; Zhao, Xiaohong; Fiskus, Warren et al. (2012) Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell 22:506-23
Fiskus, Warren; Rao, Rekha; Balusu, Ramesh et al. (2012) Superior efficacy of a combined epigenetic therapy against human mantle cell lymphoma cells. Clin Cancer Res 18:6227-38
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Cheng, Fengdong; Wang, Hongwei; Horna, Pedro et al. (2012) Stat3 inhibition augments the immunogenicity of B-cell lymphoma cells, leading to effective antitumor immunity. Cancer Res 72:4440-8
Bergman, Joel A; Woan, Karrune; Perez-Villarroel, Patricio et al. (2012) Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth. J Med Chem 55:9891-9
Zhang, X; Chen, X; Lin, J et al. (2012) Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas. Oncogene 31:3002-8

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