Ji Hongfei, Niu Xingjian, Yin Lei, Wang Yiran, Huang Lan, Xuan Qijia, Li Liru, Zhang Han, Li Jingtong, Yang Yue, An Weiwei, Zhang Qingyuan
Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin, China.
Heilongjiang Academy of Medical Sciences, Harbin, China.
Cell Physiol Biochem. 2018;45(3):951-961. doi: 10.1159/000487288. Epub 2018 Feb 2.
BACKGROUND/AIMS: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease, and is the most common type of lymphoma in adults. Although significant progress in treatment has been made using chemotherapy combinations, there exist a large amount of relapse or refractory cases. Thus, effective clinical biomarkers for DLBCL are urgently needed. Our study aims to explore the predictive significance of using the immune response to tumor burden ratio [defined as the lymphocyte to monocyte ratio (LMR)/lactate dehydrogenase (LDH) levels] in 184 DLBCL patients and the potential mechanism underlying the use of the LMR to tumor burden ratio in predicting patient survival.
The correlation between serum LDH levels and tumor levels assessed by PET-CT was determined using Spearman's correlation analysis. Clinical data from 184 DLBCL patients was assessed using receiver operating characteristic curve analysis and survival analysis. The potential correlation between tumor burden and lymphocytes or monocytes was analyzed by immunohistochemical staining, flow cytometry, and ELISA analysis of patient samples. In addition, we performed in vitro studies to further determine the effects of tumor burden on the anti-tumor activity of T lymphocytes.
We observed that serum LDH was an excellent surrogate marker of tumor burden in DLBCL patients, and that the ratio of LMR to LDH was an independent prognostic biomarker capable of predicting survival in DLBCL patients. Further analysis showed that a high tumor burden was correlated with decreased Ki67 expression in T cells, either in the solid tumor tissue or in the circulating blood. In addition, based on an in vitro co-culture study, a higher tumor burden led to the suppression of the anti-tumor response of T cells. Furthermore, we found that a higher tumor burden was correlated with the differentiation of monocytes to tumor associated macrophages in the tumor micro-environment. Both results demonstrate the importance of considering both the immune system and tumor burden for prognostic analysis.
Our study has identified a novel clinical biomarker, namely, the immune response to tumor burden ratio, that can be used to distinguish survival outcomes in DLBCL patients, and demonstrated the potential mechanism underlying the use of this biomarker, that incorporates both the immune system and tumor burden, for use in future clinical applications.
背景/目的：弥漫性大B细胞淋巴瘤（DLBCL）是一种侵袭性疾病，是成人中最常见的淋巴瘤类型。尽管使用联合化疗在治疗方面取得了显著进展，但仍存在大量复发或难治性病例。因此，迫切需要有效的DLBCL临床生物标志物。我们的研究旨在探讨免疫反应与肿瘤负荷比值[定义为淋巴细胞与单核细胞比值（LMR）/乳酸脱氢酶（LDH）水平]在184例DLBCL患者中的预测意义，以及LMR与肿瘤负荷比值预测患者生存的潜在机制。
采用Spearman相关性分析确定血清LDH水平与PET-CT评估的肿瘤水平之间的相关性。使用受试者工作特征曲线分析和生存分析评估184例DLBCL患者的临床数据。通过免疫组织化学染色、流式细胞术和患者样本的ELISA分析，分析肿瘤负荷与淋巴细胞或单核细胞之间的潜在相关性。此外，我们进行了体外研究，以进一步确定肿瘤负荷对T淋巴细胞抗肿瘤活性的影响。
我们观察到血清LDH是DLBCL患者肿瘤负荷的一个优良替代标志物，LMR与LDH的比值是能够预测DLBCL患者生存的独立预后生物标志物。进一步分析表明，无论是在实体瘤组织还是循环血液中，高肿瘤负荷均与T细胞中Ki67表达降低相关。此外，基于体外共培养研究，更高的肿瘤负荷导致T细胞抗肿瘤反应受到抑制。此外，我们发现更高的肿瘤负荷与肿瘤微环境中单核细胞向肿瘤相关巨噬细胞的分化相关。这两个结果均证明了在预后分析中同时考虑免疫系统和肿瘤负荷的重要性。
我们的研究确定了一种新的临床生物标志物，即免疫反应与肿瘤负荷比值，可用于区分DLBCL患者的生存结果，并证明了这种结合免疫系统和肿瘤负荷的生物标志物在未来临床应用中的潜在机制。
