Interleukin 10(IL10) proximal promoter polymorphisms beyond clinical response in classical Hodgkin lymphoma: Exploring the basis for the genetic control of the tumor microenvironment

Abstract

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/mm2, 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.

The circuitry of the tumor microenvironment in adult and pediatric Hodgkin lymphoma: cellular composition, cytokine profile, EBV, and exosomes

“…High levels of serum IL‐10 and polymorphisms are associated with B symptoms and adverse therapeutic response in both adults and childhood HL indicating its direct role in cHL pathogenesis 54 . Additionally, polymorphism in IL‐10 affects host genetic susceptibility and influences the composition of the TME in pediatric HL 55 . IL‐6 expression in the background cells is an independent poor predictor of response in pediatric HL 52 .…”

IL10 as Cancer Biomarker

“…Nevertheless, genotypes of the −592 SNP showed no association with IL10 mRNA expression. However, −1082AACAG genotypes, ATA haplotype, and the presence of the −592AA genotype were associated with unfavorable prognosis [47,96].…”

“…Hodgkin's disease presented sera elevated IL-10 levels on range 4.5-225.6 pg/ ml, suggesting that IL-10 could be an independent prognostic factor and correlates to poor survival [46]. Lymph nodes from pediatric patients with Hodgkin's disease express high levels of IL-10 mRNA where there were associated with an unfavorable prognosis [47,48]. For the study of sera levels in 153 patients with Non-Hodgkin's disease, IL-10 was detectable with a similar frequency in all subtypes and all clinical stages.…”

“…Patients IL-10 levels Healthy donor References Melanoma 15-480 pg/ml <3.0 pg/ml [35] 8.75 pg/ml <3.0 pg/ml [39] 24.3 ng/ml 3.4 ng/ml [41] Gastric cancer 6.3 ng/ml 3.4 ng/ml [41] 12.5 pg/ml 4.0 pg/ml [40] 27.52 pg/ml <12 np/ml [51] 19.6 pg/ml 9.2 pg/ml [52] >21.0 pg/ml <3.0 pg/ml [53] Pancreatic cancer 6.8 ng/ml 3.4 ng/ml [41] >10.0 pg/ml ND [54] >9 clinical outcome imparted by IL10 genetic variants may be mediated by effects on the tumor micro-environment composition or modulation [47]. The possibility that SNPs participate in the development, establishment, and the prognosis of cancer has been investigated by numerous research groups and includes several group malignances.…”

Cytokine-based Cancer Immunotherapy: Challenges and Opportunities for IL-10

“…While these were limited in cohort size and cause-and-effect relationships, they incited investigation. Given IL-10's importance in cancers (40)(41)(42), the impact of SNPs on molecular functioning is crucial.…”