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Targeting IL-10 abrogates ATL LIC
of IL-10, an anti-inflammatory cytokine that impedes the pro-inflammatory response. Targeted therapies hamper- ing IL-10 production by ATL cells activate an innate immune response which eradicates the disease through abrogation of LIC activity.
Oncogene addiction is a specific feature of LIC,34 sug- gesting that, at least in malignancies with a single rate-lim- iting genetic event such as some leukemias, oncogene degradation could be used to eradicate LIC and, secondar- ily, the disease.21,35,36 It has been suggested that ATL cells depend on Tax expression for their survival and long-term self-renewal.10,11 However, Tax expression is barely detectable in patients with ATL, likely due to the defect of the provirus in ATL cells and 5’ long terminal repeat selec- tive heavy CpG methylation in some patients. Yet, tran- sient bursts of Tax expression take place in a small fraction of HTLV-1-infected non-malignant or ATL cells.9,11 Nonetheless, this finding still necessitates validation in pri- mary ATL cells. Moreover, in most reported cases, Tax expression was analyzed in cells from peripheral blood but not from lymph nodes, spleen or bone marrow where LIC might be located. In our model, AS/IFNα-induced loss of IL-10 production and LIC activity were rescued upon co-treatment with a proteasome inhibitor, suggesting that the curative effect of AS/IFNα in ATL involves Tax degra- dation by the proteasome.10,21 Unfortunately, the unde- tectable level of Tax protein in tax transgenic murine ATL cells precludes a direct demonstration of therapy-induced Tax degradation in vivo. To overcome this in vivo limitation, we knocked down Tax expression in human ATL-derived cell lines expressing different baseline levels of Tax pro- tein. We demonstrated that extinction of Tax significantly affected IL-10 production, regardless of baseline Tax pro- tein expression, confirming that IL-10 is a downstream tar- get of Tax. Our findings, along with recently reported data on the upregulation of IL-10 expression by the other HTLV-1 regulatory protein HBZ,33 highlights the critical role of IL-10 in HTLV-1 infection and the pathogenesis of ATL.
One limitation of our model is that the immune-pheno- type of the malignant cells in our model (exclusively CD4– CD8– cells) may not reflect that of the majority of ATL cells. In this model, the lack of adaptive immunity allowed us to unravel the critical role of innate immunity in AS/IFNα-induced eradication of ATL LIC activity. Nevertheless, therapy-induced loss of IL-10 production likely also activates adaptive immunity in patients with
ATL. Similarly, HTLV-1-infected non-malignant cells nor- mally present in patients with ATL are not encountered in tax transgenic mice. These HTLV-1-infected non-malig- nant cells can be a source for Tax-dependent IL-10 produc- tion in patients with ATL, allowing long-term self-renewal of malignant cells in niches, even in the minority of patients with a defective provirus that lost the ability to express Tax in the malignant cells. Finally, we cannot dis- miss the possibility that HTLV-1-negative cells may also participate in the production of IL-10 in patients with ATL and that these may also be targeted by AS/IFNα. However, our results in tax transgenic mice are similar to those obtained in ATL-derived cell lines, freshly isolated cells from ATL patients and, importantly, patients with ATL treated with AS/IFNα/AZT.24
In conclusion, collectively our results provide a strong rationale for clinical trials combining AS/IFNα with anti- IL-10 antibodies in patients with ATL. Furthermore, week- ly examination of untreated secondary mice enables a detailed exploration of therapy-induced response to tar- geted agents in vivo, and disentangles the sequence of events resulting from the effect of treatment on leukemic cells and their environment.
Disclosures
No conflicts of interest to disclose.
Contributions
HEH, RH, JB, MC, AM and AA performed experiments; HEH, MES, GZ, HH, WH, HdT, OH and AB analyzed results; HEH and RH created the figures; HEH, HdT, OH and AB designed the research and wrote the paper.
Acknowledgments
We thank Drs. Youmna Kfoury and Renaud Mahieux for their critical reading of the manuscript. This manuscript was edited by Life Science Editors.
Funding
This work was supported by the American University of Beirut Medical Practice Plan, the University Research Board, the Lebanese National Council for Scientific Research, the Lady TATA Memorial Trust; the European Research Council (Senior Grant 268729–STEMAPL) (to HdT), the Ligue Nationale Contre le Cancer, Centre National de la Recherche Scientifique, Association de Recherche Contre le Cancer, Institut National Contre le Cancer, and Cancerople Ile de France (to OH).
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