The Role of Monocytes in non-Hodgkin Lymphoma

肿瘤微环境在非霍奇金淋巴瘤（NHL）中起重要作用， 肿瘤内免疫细胞在淋巴瘤病理学中的作用一直被严重低估。瘤内 单核细胞和巨噬细胞是特别重要的，我们的数据表明， NHL中的单核细胞是高度免疫抑制性的并支持恶性细胞生长。 在前期工作中，我们发现外周血单核细胞（SMCs）中有大量的抑制性单核细胞（SMCs）。 淋巴瘤患者的血液和肿瘤微环境，促进淋巴瘤细胞的存活。SMCs 保护淋巴瘤细胞免于化疗诱导的细胞死亡，并促进淋巴瘤细胞植入 严重联合免疫缺陷（SCID）小鼠。此外，我们发现淋巴结内的SMC 表达免疫抑制配体，包括B7-H1（PD-L1，CD 273），抑制正常T细胞增殖， 促进FoxP 3+调节性T细胞的诱导。这些初步研究表明，SMC具有 对恶性NHL细胞和非恶性肿瘤内T细胞的作用。 根据我们的研究结果，我们假设免疫系统和恶性肿瘤之间的交叉点 NHL中的细胞是SMC。在这项提案中，我们计划了解单核细胞是否特异性地 募集到淋巴瘤的部位，哪些特异性趋化因子可以被抑制以防止SMC迁移; 淋巴瘤细胞如何诱导SMC支持其恶性细胞生长并抑制宿主的抗肿瘤活性 免疫;以及是否促进单核细胞/巨噬细胞成熟或抑制它们与 其它细胞，特别是在单克隆抗体存在下，提高了它们的抗肿瘤功能。后 完成这个项目，我们希望有一个更好的了解单核细胞的作用和他们的 NHL中的后代。总的来说，我们的研究结果可能会产生重大影响， 单核细胞导向的治疗方法，淋巴瘤患者。

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.