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.
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.
|McPhail, Ellen D; Maurer, Matthew J; Macon, William R et al. (2018) Inferior survival in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements is not associated with MYC/IG gene rearrangements. Haematologica 103:1899-1907|
|Hill, Brian T; Nastoupil, Loretta; Winter, Allison M et al. (2018) Maintenance rituximab or observation after frontline treatment with bendamustine-rituximab for follicular lymphoma. Br J Haematol :|
|Kleinstern, Geffen; Camp, Nicola J; Goldin, Lynn R et al. (2018) Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. Blood 131:2541-2551|
|J Pelletier, Daniel; O'Donnell, Michael; Stone, Mary Seabury et al. (2018) Intravesicular taxane-induced dermatotoxicity in a 78-year-old man with urothelial carcinoma and primary cutaneous anaplastic large cell lymphoma. J Cutan Pathol 45:453-457|
|Thanarajasingam, Gita; Minasian, Lori M; Baron, Frederic et al. (2018) Beyond maximum grade: modernising the assessment and reporting of adverse events in haematological malignancies. Lancet Haematol 5:e563-e598|
|Ravi, Praful; Kumar, Shaji K; Cerhan, James R et al. (2018) Defining cure in multiple myeloma: a comparative study of outcomes of young individuals with myeloma and curable hematologic malignancies. Blood Cancer J 8:26|
|McMaster, Mary L; Berndt, Sonja I; Zhang, Jianqing et al. (2018) Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia. Nat Commun 9:4182|
|Pophali, Priyanka A; Ip, Andrew; Larson, Melissa C et al. (2018) The association of physical activity before and after lymphoma diagnosis with survival outcomes. Am J Hematol 93:1543-1550|
|Shenoy, Niraj; Creagan, Edward; Witzig, Thomas et al. (2018) Ascorbic Acid in Cancer Treatment: Let the Phoenix Fly. Cancer Cell 34:700-706|
|Maurer, M J; Habermann, T M; Shi, Q et al. (2018) Progression-free survival at 24 months (PFS24) and subsequent outcome for patients with diffuse large B-cell lymphoma (DLBCL) enrolled on randomized clinical trials. Ann Oncol 29:1822-1827|
Showing the most recent 10 out of 387 publications