The Role of Monocytes in Non-Hodgkin Lymphoma
The tumor microenvironment plays an important role in non-Hodgkin lymphoma, and the role that intratumoral immune cells play in the pathology of lymphoma has been significantly understated.
The University of Iowa/Mayo Clinic Lymphoma SPORE's research project on monocytes in non-Hodgkin lymphoma is expected to lead to a greater understanding of the role of monocytes and their progeny in non-Hodgkin lymphoma.
The project's findings are likely to lead to an effective monocyte-directed therapeutic approach for patients with lymphoma.
Intratumoral monocytes and macrophages are particularly important. Data from the Lymphoma SPORE research project demonstrate that intratumoral monocytes in non-Hodgkin lymphoma are highly immunosuppressive and support malignant cell growth.
In preliminary work, the project team found that suppressive monocytic cells (SMCs) are abundant within the peripheral blood and tumor microenvironment in patients with lymphoma 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.
The team also found that suppressive monocytic cells 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 suppressive monocytic cells have an effect on both malignant non-Hodgkin lymphoma cells and nonmalignant intratumoral T cells.
Based on these results, this Lymphoma SPORE research project hypothesizes that suppressive monocytic cells are the intersection between the immune system and the malignant cell in non-Hodgkin lymphoma.
The University of Iowa/Mayo Clinic Lymphoma SPORE project team plans to determine:
- 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 anti-tumor immunity
- Whether promoting monocyte and macrophage maturation or inhibiting their interaction with other cells, particularly in the presence of monoclonal antibodies, improves their anti-tumor function
The Role of Monocytes in Non-Hodgkin Lymphoma research project has three main aims.
Aim 1: Define the mechanisms that result in the recruitment of monocytes to sites of lymphoma
The project is studying whether intratumoral monocytes/macrophages migrate in response to chemotactic ligands and establish a role for malignant cells in their recruitment. The project is also investigating whether monocytes undergo phenotypic and functional changes when recruited to lymphoma sites.
Aim 2: Determine the mechanisms by which monocytes promote malignant B-cell survival and suppress intratumoral immune effector cells
The project is identifying the mechanisms responsible for the support of malignant cell growth and viability and the mechanisms responsible for suppression of effector T-cell function. The project is also investigating whether intratumoral monocytes remain immunosuppressive in the presence of monoclonal antibodies targeting lymphoma cells.
Aim 3: Block suppressive monocyte formation to improve immunity and impact clinical outcome
The project is researching whether maturation of intratumoral monocytes suppresses their ability to support lymphoma cell growth and survival, reverses their immunosuppressive properties, and increases antibody-dependent cell-mediated cytotoxicity.
The leader of this Lymphoma SPORE project is: