Vera-Lozada Gabriela, Minnicelli Carolina, Segges Priscilla, Stefanoff Gustavo, Kristcevic Flavia, Ezpeleta Joaquin, Tapia Elizabeth, Niedobitek Gerald, Barros Mário Henrique M, Hassan Rocio
Oncovirology Laboratory, Bone Marrow Transplantation Center (CEMO), Department of Clinical Analysis and Toxicology, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil.
Universidade Federal do Rio Grande do Norte (UFRN), Natal RN, Brazil.
Oncoimmunology. 2018 Mar 29;7(5):e1389821. doi: 10.1080/2162402X.2017.1389821. eCollection 2018.
Interleukin-10 (IL10) is an immune regulatory cytokine. Single nucleotide polymorphisms (SNPs) in IL10 promoter have been associated with prognosis in adult classical Hodgkin lymphoma (cHL). We analyzed IL10 SNPs -1082 and -592 in respect of therapy response, gene expression and tumor microenvironment (TME) composition in 98 pediatric patients with cHL. As confirmatory results, we found that -1082AA/AG; -592CC genotypes and ATA haplotype were associated with unfavourable prognosis: Progression-free survival (PFS) was shorter in -1082AA+AG (72.2%) than in GG patients (100%) (P = 0.024), and in -592AA (50%) and AC (74.2%) vs. CC patients (87.0%) (P = 0.009). In multivariate analysis, the -592CC genotype and the ATA haplotype retained prognostic impact (HR: 0.41, 95% CI 0.2-0.86; P = 0.018, and HR: 3.06 95% CI 1.03-9.12; P = 0.044, respectively). Our analysis further led to some new observations, namely: (1) Low IL10 mRNA expression was associated with -1082GG genotype (P = 0.014); (2) IL10 promoter polymorphisms influence TME composition;-1082GG/-592CC carriers showed low numbers of infiltrating cells expressing MAF transcription factor (20 vs. 78 and 49 vs. 108 cells/mm, respectively; P< 0.05); while ATA haplotype (high expression) associated with high numbers of MAF+ cells (P = 0.005). Specifically, -1082GG patients exhibited low percentages of CD68+MAF+ (M2-like) intratumoral macrophages (15.04% vs. 47.26%, P = 0.017). Considering ours as an independent validation cohort, our results give support to the clinical importance of IL10 polymorphisms in the full spectrum of cHL, and advance the concept of genetic control of microenvironment composition as a basis for susceptibility and therapeutic response.
白细胞介素-10（IL10）是一种免疫调节细胞因子。IL10启动子中的单核苷酸多态性（SNP）与成人经典型霍奇金淋巴瘤（cHL）的预后相关。我们分析了98例儿童cHL患者中IL10的SNP -1082和-592与治疗反应、基因表达及肿瘤微环境（TME）组成的关系。作为验证结果，我们发现-1082AA/AG；-592CC基因型和ATA单倍型与不良预后相关：-1082AA+AG患者的无进展生存期（PFS）（72.2%）短于GG患者（100%）（P = 0.024），-592AA（50%）和AC（74.2%）患者的PFS短于CC患者（87.0%）（P = 0.009）。在多因素分析中，-592CC基因型和ATA单倍型仍具有预后影响（HR：0.41，95%CI 0.2 - 0.86；P = 0.018，以及HR：3.06，95%CI 1.03 - 9.12；P = 0.044）。我们的分析还得出了一些新的观察结果，即：（1）低IL10 mRNA表达与-1082GG基因型相关（P = 0.014）；（2）IL10启动子多态性影响TME组成；-1082GG/-592CC携带者表达MAF转录因子的浸润细胞数量较少（分别为20对78以及49对108个细胞/mm；P<0.05）；而ATA单倍型（高表达）与大量MAF+细胞相关（P = 0.005）。具体而言，-1082GG患者肿瘤内CD68+MAF+（M2样）巨噬细胞的百分比低（15.04%对47.26%，P = 0.017）。鉴于我们的研究为独立验证队列，我们的结果支持了IL10多态性在整个cHL谱中的临床重要性，并推进了将微环境组成的基因控制作为易感性和治疗反应基础的概念。
