The tumor microenvironment plays an important role in non-Hodgkin lymphoma (NHL) and the role intratumoral immune cells play in the pathology of lymphoma has been significantly understated. Intratumoral monocytes and macrophages are particularly important and our data demonstrate that intratumoral monocytes in NHL are highly immunosuppressive and support malignant cell growth. In preliminary work, we found that suppressive monocytic cells (SMCs) are abundant within the peripheral blood and tumor microenvironment in lymphoma patients and promote the survival of lymphoma cells. SMCs protect lymphoma cells from chemotherapy-induced cell death and promote lymphoma cell engraftment into severe combined immunodeficient (SCID) mice. Furthermore, we found that SMCs within lymph nodes express immunosuppressive ligands including B7-H1 (PD-L1, CD273), inhibit normal T-cell proliferation and promote the induction of FoxP3+ regulatory T cells. These preliminary studies suggest that SMCs have an effect on both malignant NHL cells and non-malignant intratumoral T-cells. Based on our results, we hypothesize that the intersection between the immune system and the malignant cell in NHL is the SMCs. In this proposal, we plan to understand whether monocytes are specifically recruited to sites of lymphoma and which specific chemokines could be inhibited to prevent SMC migration; how lymphoma cells induce SMCs to support their malignant cell growth and to suppress the host's antitumor immunity;and whether promoting monocyte/macrophage maturation or inhibiting their interaction with other cells, particularly in the presence of monoclonal antibodies, improves their anti-tumor function. Upon completion of this project, we expect to have a greater understanding of the role of monocytes and their progeny in NHL. Collectively our findings are likely to have a major impact by leading to an effective monocyte-directed therapeutic approach for patients with lymphoma.

Public Health Relevance

The monocyte-macrophage system is critical in the host's response to pathogens and inflammation. In lymphoma patients, however, there is a significant population of immunosuppressive monocytic cells present in peripheral blood and lymph nodes that promotes the survival of malignant cells. The proposed studies will provide a comprehensive understanding of the role of suppressive monocytes in lymphoma, allowing us to intervene and modulate monocyte function on multiple levels leading to novel therapeutic approaches for lymphoma patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA097274-12
Application #
8561351
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
12
Fiscal Year
2013
Total Cost
$263,720
Indirect Cost
$23,439
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Makkouk, Amani; Weiner, George J (2015) Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge. Cancer Res 75:10-May
Xing, Xiaoming; Flotte, Thomas J; Law, Mark E et al. (2015) Expression of the chemokine receptor gene, CCR8, is associated With DUSP22 rearrangements in anaplastic large cell lymphoma. Appl Immunohistochem Mol Morphol 23:580-9
Witzig, Thomas E; Maurer, Matthew J; Stenson, Mary J et al. (2014) Elevated serum monoclonal and polyclonal free light chains and interferon inducible protein-10 predicts inferior prognosis in untreated diffuse large B-cell lymphoma. Am J Hematol 89:417-22
Workalemahu, Grefachew; Wang, Hong; Puan, Kia-Joo et al. (2014) Metabolic engineering of Salmonella vaccine bacteria to boost human V?2V?2 T cell immunity. J Immunol 193:708-21
Cerhan, James R; Berndt, Sonja I; Vijai, Joseph et al. (2014) Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat Genet 46:1233-8
Hu, Guangzhen; Lou, Zhenkun; Gupta, Mamta (2014) The long non-coding RNA GAS5 cooperates with the eukaryotic translation initiation factor 4E to regulate c-Myc translation. PLoS One 9:e107016
Aschebrook-Kilfoy, Briseis; Cocco, Pierluigi; La Vecchia, Carlo et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for mycosis fungoides and Sézary syndrome: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:98-105
Skibola, Christine F; Slager, Susan L; Berndt, Sonja I et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for adult acute lymphocytic leukemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:125-9
Vajdic, Claire M; Landgren, Ola; McMaster, Mary L et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:87-97
Morton, Lindsay M; Slager, Susan L; Cerhan, James R et al. (2014) Etiologic heterogeneity among non-Hodgkin lymphoma subtypes: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:130-44

Showing the most recent 10 out of 229 publications