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.
Highlights
The immune response following Toll-like receptor 9 (TLR9) engagement is highly desirable for cancer treatment.[8]
We were mainly interested in those involved in cytokine and chemokine expression (CXCL10), B-cell activation (CD40), transcription (NF-kB) and apoptosis (FAS)
We analyzed the effects of TLR9 agonists on Burkitt’s lymphoma (BL) cell lines as an in vitro model for B-cell tumor
Summary
The immune response following TLR9 engagement is highly desirable for cancer treatment.[8]. Clinical trials have shown promising results for the treatment of various cancer types with CpG ODNs.[9] Their effects can be indirect by enhancing the anti-tumor immune response or direct by inducing apoptosis in the malignant cells. B-cell activation can eventually lead to activation-induced cell death of cancer cells and support anti-cancer treatment.[10] the TLR9 agonist effects vary strongly between B-cell cancer types, and the responses of B-cell lymphomas to ODN CpG-2006 show high variability.[11] the effects of CpG ODNs on B-cell malignancies are not predictable. Up to 40% of BL in human immunodeficiency virus carriers harbor EBV.[17] As latent EBV exhibits unique growth transformation potential on B cells in vitro[18] and TLR9 triggering enhances EBV-induced B-cell transformation[19] and promotes latent EBV in vitro,[15,16] TLR9 stimulation in the treatment of EBV-positive BL could provoke detrimental rather than beneficial outcomes. The responses of TLR9 SNPs in B-cell tumors to CpG ODN treatment are not reported
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