Abstract
<div>Abstract<p>Natural killer (NK) cells provide a natural defense against MHC-I–negative tumors, such as melanoma. Donor lymphocyte infusion (DLI) containing NK cells, a form of adoptive immunotherapy used after allogenic bone marrow transplantation (allo-BMT), promotes antitumor immune responses but is often associated with life-threatening complications such as graft-versus-host disease (GvHD). Here, we showed that without prior allo-BMT, DLI provoked melanoma control associated with the infiltration and persistence of the transferred NK cells. This allograft acceptance did not correlate with an increase of GvHD; instead it correlated with the expansion and activation of tumor-infiltrating NK cells that expressed the cytotoxic molecules (e.g., IFNγ and granzyme B) and maturation signatures (e.g., CD11b<sup>hi</sup>CD27<sup>lo</sup> and KLRG<sup>hi</sup>/CD43<sup>hi</sup>). The development of beneficial tumor-infiltrating NK cells of DLI origin required host CD4<sup>+</sup> T-cell help in part by producing IL2, as well as by limiting regulatory CD4<sup>+</sup> T cells (Treg). IL2 blockade impaired the NK-dependent melanoma control, which could not be rescued by IL2 administration beyond CD4<sup>+</sup> T-cell help. Our findings linked NK allograft acceptance–CD4<sup>+</sup> T-cell help crosstalk to melanoma development without the need of allo-BMT. We thereby helped define that tumor-infiltrating NK cells of DLI origin may serve as effective therapeutic targets for controlling melanoma.</p></div>
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