<h3>Background</h3> IL-15 has been highlighted as potent therapeutic tool for cancer immunotherapy, due to its central role in the activation of antitumor immunity.¹ IL-15 is signalized via IL-15/IL-15Rα complex in a trans-presentation fashion, activating natural killer (NK) cells and supporting survival of memory CD8 T cells. IL-15 outperformed antitumor activity as compared to IL-2 in melanoma spheroids, via expansion of NK and CD8.² However, antitumoral action of IL-15, has not been sufficiently elucidated in a human immunological context in vivo. <h3>Methods</h3> We used immunodeficient NOD.Rag1^null.IL-2Ry^null (NRG) mice, reconstituted with a functional human immune system in two models: human peripheral blood (PB) mononuclear cells (PBMC) transfer (HuPBL) and human umbilical cord blood hematopoietic stem cells (HSC) transplant (HuHSC). In HuPBL, 8–10 weeks-old mice (n=6) were subcutaneously implanted (right flank) with human melanoma A375 expressing a secreting form of IL-15/IL-15Rα trimerized complex (A375-IL-15s). PBMC was intravenously injected 72 hours later. In HuHSC, 4 weeks-old mice (n=6) were sublethally irradiated and transplanted with CD34+ cells HSC. 14 weeks post-transplant, (&gt;10% CD3+ in CD45+), A375-IL-15s were implanted. Unmodified A375 (A375-WT) were used as controls in both models. Tumor growth and human hematopoietic cells in PB were weekly monitored. Tumor tissue and lymphoid organs were recovered and human infiltrating cells were assessed. <h3>Results</h3> Tumor growth dramatically decrease in A375-IL-15s mice as compared to A375-WT in both HuPBL and HuHSC. Of note, transfer of PBMNC led to expansion of human T cells in PB along with signs of xeno-graft vs. host disease (xenoGvHD) in both IL-15s and WT groups in the HuPBL model. However, reduced tumor growth was exclusively associated with strong infiltration of CD3 in IL-15s presence, as compared to controls. Conversely, in the HuHSC model, IL-15s led to enhanced tumor infiltration of human T and NK cells, and reduced myeloid cells. The later was associated with significant expansion of these populations in PB, and absence of xenoGv-HD. Interestingly, NK profile in PB was predominantly CD16+ whereas in tumor infiltrate was mostly CD56+. Conversely, myeloid cells were significantly present in control WT tumors and PB. <h3>Conclusions</h3> Here, we compared two humanized immune systems in mice bearing human melanoma, to demonstrate the potent antitumor effects of human IL-15/IL15Rα, via enhanced cytotoxic CD8 T and NK responses. IL-15 soluble complex might disrupt the immune tolerance in A375 melanoma by increasing NK and T cell trafficking, tumor infiltration and stimulation of cytotoxic responses in a human tumor context. <h3>References</h3> Cheever MA. Twelve immunotherapy drugs that could cure cancers. <i>Immunol Rev</i> 2008 Apr;<b>222</b>:357–68. Awad RM, De Vlaeminck Y, Meeus F, Ertveldt T, Zeven K, Ceuppens H, Goyvaerts C, Verdonck M, Salguero G, Raes G, Devoogdt N, Breckpot K. In vitro modelling of local gene therapy with IL-15/IL-15Rα and a PD-L1 antagonist in melanoma reveals an interplay between NK cells and CD4+ T cells. <i>Sci Rep</i> 2023 Nov 3;<b>13</b>(1):18995. doi: 10.1038/s41598-023-45948-w. PMID: 37923822; PMCID: PMC10624833. <h3>Ethics Approval</h3> This study was approved by the 'Ethics and Research Committee' of the Subred Sur Occidente E.S.E.; approval number 12/2023 for the use of human material. This study was also approved by the 'Committee for the Use and Care of Laboratory Animal' of the National Institute of Health; approval number 03/2023 for animal use.