Macrophage polarization reflects T cell composition of tumor microenvironment in pediatric classical Hodgkin lymphoma and has impact on survival.
Macrophage polarization reflects T cell composition of tumor microenvironment in pediatric classical Hodgkin lymphoma and has impact on survival.
复制标题
DOI：
10.1371/journal.pone.0124531
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Niedobitek G
中科院分区：
文献类型：
--
作者：
Barros MH;Segges P;Vera-Lozada G;Hassan R;Niedobitek G
巨噬细胞与经典型霍奇金淋巴瘤(CHL)的发病机制有关，并被认为对预后有负面影响。大多数关于巨噬细胞在CHL中的作用的研究都依赖于通过通用的巨噬细胞抗原来识别巨噬细胞，如CD68。因此，我们用免疫组织化学双重染色的方法，结合CD68或CD163与pSTAT1(M1样)或CMAF(M2样)，对100例儿童慢性粒细胞白血病(PCHL)的巨噬细胞极化进行了原位分析。M1或M2极化微环境的定义是一个种群超过另一个种群(>；1.5)。RT-qPCR检测STAT1和LyZ基因的表达。14岁组和EBV阳性组CD68+pSTAT1+细胞数分别高于年龄较大组和EBV阴性组(P=0.01和P=0.02)。CD8+/FOXP3+比值定义的细胞毒性肿瘤微环境与CD68+pSTAT1+(P=0.025)和CD163+pSTAT1+巨噬细胞数(P<；0.0005)相关。STAT1和LyZ表达水平与CD68+pSTAT1+巨噬细胞数呈正相关。EBV+CHL病例表现出类似于Th1介导的炎性疾病的主要M1极化微环境，而EBV-ch1表现出接近Th2介导的炎症性疾病的主要M2极化微环境。CD163+pSTAT1+巨噬细胞数高者总生存期(OS)较好(P=0.02)，CD163+CMAF+巨噬细胞数多者无进展生存期(PFS)较差(P=0.02)。CD163+pSTAT1+/CD163+CMAF+Ratio的优势类M1极化与较好的OS相关(P=0.037)。总之，PCHL的巨噬细胞极化与普遍的局部T细胞反应相关，并可能受到肿瘤细胞EBV状态的影响。此外，M1样和M2样巨噬细胞对PCHL的预后有不同的影响。
Macrophages have been implicated in the pathogenesis of classical Hodgkin lymphoma (cHL) and have been suggested to have a negative impact on outcome. Most studies addressing the role of macrophages in cHL have relied on identification of macrophages by generic macrophage antigens, e.g., CD68. We have therefore conducted an in situ analysis of macrophage polarization in a series of 100 pediatric cHL (pcHL) cases using double staining immunohistochemistry, combining CD68 or CD163 with pSTAT1 (M1-like) or CMAF (M2-like). M1- or M2-polarised microenvironment was defined by an excess of one population over the other (>1.5). Expression of STAT1 and LYZ genes was also evaluated by RT-qPCR. Patients <14 years and EBV+ cases displayed higher numbers of CD68+pSTAT1+ cells than older children and EBV- cases, respectively (P=0.01 and P=0.02). A cytotoxic tumor microenvironment, defined by a CD8+/FOXP3+ ratio >1.5 was associated with higher numbers of CD68+pSTAT1+ (P=0.025) and CD163+pSTAT1+ macrophages (P<0.0005). Levels of STAT1 and LYZ expression were associated with the numbers of CD68+pSTAT1+ macrophages. EBV+ cHL cases disclosed a predominant M1 polarized microenvironment similar to Th1 mediated inflammatory disorders, while EBV- cHL showed a predominant M2 polarized microenvironment closer to Th2 mediated inflammatory diseases. Better overall-survival (OS) was observed in cases with higher numbers of CD163+pSTAT1+ macrophages (P=0.02) while larger numbers of CD163+CMAF+ macrophages were associated with worse progression-free survival (PFS) (P=0.02). Predominant M1-like polarization as disclosed by CD163+pSTAT1+/CD163+CMAF+ ratio > 1.5 was associated with better OS (P= 0.037). In conclusion, macrophage polarization in pcHL correlates with prevalent local T cell response and may be influenced by the EBV-status of neoplastic cells. Besides, M1-like and M2-like macrophages displayed differential effects on outcome in pcHL.