TLR9 agonists induced cell death in Burkitt's lymphoma cells is variable and influenced by TLR9 polymorphism

Abstract

Toll-like receptor 9 (TLR9) triggering is a promising novel strategy to combat cancer as it induces innate and adaptive immunity responses. B-cell lymphoma is unique in this context as tumor cells express TLR9 and may harbor latent Epstein-Barr virus (EBV), a gamma-herpesvirus with remarkable oncogenic potential when latent. Latent EBV may be promoted by TLR9 triggering via suppression of lytic EBV. Here, we elaborated an initial assessment of the impact of TLR9 triggering on EBV-positive and EBV-negative B-cell lymphoma using Burkitt's lymphoma (BL) cell lines as an in vitro model. We show that, independent of the presence of EBV, the TLR9 ligand oligodeoxynucleotide (ODN) CpG-2006 may or may not induce caspase-dependent cell death in BL cells. Moreover, ODN CpG-2006-induced cell death responses of BL cells were associated with TLR9 single-nucleotide polymorphisms (SNPs) rs5743836 or rs352140, which we detected in primary BL tumors and in peripheral blood from healthy individuals at similar frequencies. Thus, our findings suggest that the effect of TLR9 agonists on BL cells should be tested in vitro before installment of therapy and TLR9 SNPs in BL patients should be determined as potential biological markers for the therapeutic response to treatment targeting innate immunity.

The TLR9 Gene Polymorphisms and the Risk of Cancer: Evidence from a Meta-Analysis

“…After reviewing full text, 10 studies were excluded for the following reasons, three papers were reviews [5], [11], [36], two papers were relating to risk of infection during cancer therapy [37], [38], one paper was relating to outcome of AML patients transplanted from HLA-identical sibling donors [39], two papers lacked of gene frequency data to calculate the ORs and 95% CI [40], [41], and two of the studies were disequilibrium from HWE in control group [13], [15]. One article evaluated two SNPs (rs352140 and rs5743836) with Burkitt’s lymphoma risk [24], and genotype distribution in the control of rs352140 was inconsistent with HWE (P<0.05). Therefore, we extracted the data relating to rs5743836 for our meta-analysis.…”

“…Study characteristics were summarized in Table 1. As shown in table 1, five studies were available for rs352140 [14], [16], [17], [22], [23], ten studies were available for rs5743836 [16], [20], [22], [24]–[27], and four studies were available for rs187084 [2], [16], [26], [27]. Those include studies in Germany, Poland, Netherlands, Greece, Croatia, Portugal, USA, Australia, India and China.…”

“…Alternatively, TLR9 functions through the myeloid differentiation primary response protein 88 (MyD88)-dependent pathway leading to NF-kappa-B (NF-kB) activation, cytokine secretion and the inflammatory response [12], [13]. In the past years, numerous genetic association studies have explored the role of TLR9 gene polymorphisms in various cancers, including bladder cancer [14], prostate cancer [15], acute lymphoblastic leukemia (ALL) [16], hepatocellular carcinoma (HCC) [17], gastric cancer [18]–[20], cervical cancer [2], [13], [21], Hodgkin’s lymphoma [22], breast cancer [23], burkitt’s lymphoma [24], non-Hodgkin lymphoma [25], endometrial cancer [26], esophageal cancer [20] and lymphoma [27]. Most of the studies focused on three common single nucleotide polymorphisms (SNPs), including rs352140(C/T), rs5743836 (T/C) and rs187084(C/T) (also referred to as 2848C/T, 1237T/C, and 1486C/T, respectively).…”

Association between <em>TLR-9</em> polymorphisms and colon cancer susceptibility in Saudi Arabian female patients

“…Several studies have shown that TLR-9 engagement on cluster of differentiation 4-positive (CD4 + ) T cells can enhance their survival and therefore potentiate anticancer responses by prolonging T-cell activity 14. Previous studies have indicated that TLR-9 polymorphisms may be associated with the risk of developing several types of cancers, including bladder cancer,15 prostate cancer,16–18 acute lymphoblastic leukemia,19 hepatocellular carcinoma,20 gastric cancer,21,22 cervical cancer,23 Hodgkin’s lymphoma,24 breast cancer,25 Burkitt’s lymphoma,26 non-Hodgkin’s lymphoma,27 endometrial cancer,28 esophageal cancer,23 and lymphoma 24,27,29. However, the results are inconsistent and inconclusive.…”

Associations Between TLR9 Polymorphisms and Cancer Risk: Evidence from an Updated Meta-analysis of 25,685 Subjects

“…We reviewed the titles, abstracts, and full texts of all retrieved articles through defined criteria. Finally, 19 articles were included in this study (Nieters et al, 2006;Etokebe et al, 2009;Hold et al, 2009;Mollaki et al, 2009;Ashton et al, 2010;Pandey et al, 2011;Zeng et al, 2011;Chen et al, 2012;Carvalho et al, 2012;Li et al, 2012;Mandal et al, 2012;Miedema et al, 2012;Noack et al, 2012;Roszak et al, 2012;Xie et al, 2012;Lai et al, 2013;Resler et al, 2013;Singh et al, 2013;. Since more than one case-control study was included in ten articles (Nieters et al, 2006;Hold et al, 2009;Mollaki et al, 2009;Ashton et al, 2010;Carvalho et al, 2012;Li et al, 2012;Miedema et al, 2012;Roszak et al, 2012;Lai et al, 2013;Resler et al, 2013), they were considered as separate studies in the meta-analysis.…”