Zhang Yu, Xiang Jingjing, Sheng Xianfu, Zhu Ni, Deng Shu, Chen Junfa, Yu Lihong, Zhou Yan, Lin Chenjun, Shen Jianping
Department of Hematology, First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, 310006, Hangzhou, China.
First Medical College of Zhejiang Chinese Medical University, Hangzhou, China.
Cancer Cell Int. 2021 Mar 2;21(1):141. doi: 10.1186/s12935-021-01838-7.
Diffuse large B-cell lymphoma (DLBCL) is a common type of the Non-Hodgkin lymphomas (NHLs) formed by the neoplastic transformation of mature B cells. As the first-line therapeutics, CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy and R-CHOP (Rituximab + CHOP), either using alone or in combination with GM-CSF, have achieved great efficacy in DLBCL patients. However, the underlying mechanisms are still largely unknown.
In the present study, the combination use of CHOP and R-CHOP with GM-CSF was used to evaluate their effects on the tumor immune microenvironment of DLBCL. CHOP and R-CHOP administration was found to inhibit the growth and metastasis of DLBCL, with a higher efficacy in R-CHOP-challenged DLBCL mice. The anti-tumor effect of CHOP and R-CHOP was further amplified by GM-CSF.
CHOP and R-CHOP therapeutics potentiated the anti-tumor properties of macrophages, as evidenced by the increased M1 macrophage and the decreased M2 macrophage accumulation in DLBCL-bearing mice. In a co-culture system, macrophages primed with CHOP and R-CHOP therapeutics inhibited multiple malignant behaviors of DLCBL cells. Mechanistically, CHOP/R-CHOP suppressed the activation of AKT signaling. These anti-tumor effects of CHOP/R-CHOP were all augmented by GM-CSF.
Our work provided new insights into the immune-regulatory roles of CHOP and R-CHOP in the treatment of DLBCL, as well as the synergistic effects of GM-CSF in CHOP and R-CHOP therapeutics. Although our results suggest the synergistic effect of GM-CSF on DLBCL already sensitive to CHOP and R-CHOP, however, future studies are warranted to explore the role of GM-CSF on R-CHOP-resistant DLBCL. Trial registration Not applicable.
弥漫性大B细胞淋巴瘤（DLBCL）是成熟B细胞发生肿瘤转化形成的常见非霍奇金淋巴瘤（NHL）类型。作为一线治疗方法，CHOP（环磷酰胺/阿霉素/长春新碱/泼尼松）化疗以及R-CHOP（利妥昔单抗+CHOP），单独使用或与粒细胞-巨噬细胞集落刺激因子（GM-CSF）联合使用，在DLBCL患者中均取得了显著疗效。然而，其潜在机制仍 largely 未知。
在本研究中，使用CHOP和R-CHOP与GM-CSF联合使用来评估它们对DLBCL肿瘤免疫微环境的影响。发现给予CHOP和R-CHOP可抑制DLBCL的生长和转移，在R-CHOP处理的DLBCL小鼠中疗效更高。GM-CSF进一步增强了CHOP和R-CHOP的抗肿瘤作用。
CHOP和R-CHOP治疗增强了巨噬细胞的抗肿瘤特性，这在携带DLBCL的小鼠中M1巨噬细胞增加和M2巨噬细胞积累减少得到证明。在共培养系统中，用CHOP和R-CHOP治疗预处理的巨噬细胞抑制了DLCBL细胞的多种恶性行为。机制上，CHOP/R-CHOP抑制了AKT信号通路的激活。GM-CSF增强了CHOP/R-CHOP的这些抗肿瘤作用。
我们的工作为CHOP和R-CHOP在DLBCL治疗中的免疫调节作用以及GM-CSF在CHOP和R-CHOP治疗中的协同作用提供了新的见解。尽管我们的结果表明GM-CSF对已经对CHOP和R-CHOP敏感的DLBCL有协同作用，然而，未来的研究有必要探索GM-CSF对R-CHOP耐药的DLBCL的作用。试验注册不适用。
