Background The over-expression of AATF/Che1 (Che-1) RNA polymerase II binding protein in different tumors is well known and its effect on tumorigenicity is mainly due to its central role demonstrated in the oncogenic pathways of solid tumors, where it controls proliferation and viability. In hematological context, It was demonstrated that Che-1 exerts proto-oncogenic role in B-cell-Precursor Acute Lymphoblastic Leukemia (BCP-ALL). The effect exerted by tumors overexpressing Che-1 on the immune response has not yet been investigated. We recently demonstrated the role of Che-1 on immune-system controlling the expression of the ligands and the corresponding receptors on Natural Killer (NK) cells. In depth analysis revealed that it is involved also in the production of interleukins in tumor cells.

Materials and Methods Several co-cultures experiments between NK-cells and BCP-ALL cells transduced by lentiviral vectors carrying Che-1-interfering sequence, analyzed by Western Blot, have allowed a detailed characterization of NK-cells proliferation status. Che-1 enrichment on IL-15 promoter and the evidence obtained by RNA-sequencing, showing IL-15 induction upon Che-1 interference when compared with the control condition overexpressing Che-1, suggest the presence of Che-1 in a repressive transcriptional machinery aimed to down-regulate IL-15.

Results Here, we show that Che-1 is able to modulate the proliferative status of NK-cells. In fact, we found different expression level of proliferation markers (pERK1/2, p21) in Che-1 interfered co-culture condition when compared with the control. Interestingly, in the same experimental condition we found that MYCN is overexpressed suggesting its involvement in the regulation of NK-cells proliferation. Furthermore, we found higher expression level of the common chains of IL-2 and IL-15 receptors in siChe1 co-culture condition, assuming a consequent effect on IL receptor expression on NK-cells.

Conclusions The critical equilibrium between NK-cell ligands expression on tumor cells and the interaction with NK-cell receptors is affected by Che-1 overexpression and partially restored by Che-1 interference. The evidence of a new role for Che-1 as regulator of anti-tumor immunity supports the necessity to develop approaches able to target this molecule which shows a dual tumorigenic function as cancer promoter and immune response modulator. The data regarding IL-15 modulation makes this interleukin a good candidate as regulator of Che1-dependent NK-cells proliferation and support the aim to down-regulate Che-1 in leukemia cells to affect tumor immune escape.

M. Caforio: None. N. Tumino: None. C. Sorino: None. S. Di Giovenale: None. L. Moretta: None. M. Fanciulli: None. P. Vacca: None. F. Locatelli: None. V. Folgiero: None.