Donor Lymphocyte–Derived Natural Killer Cells Control MHC Class I–Negative Melanoma

Abstract

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., IFN-gamma and granzyme B) and maturation signatures (e.g., CD11b hi CD27 lo and KLRG hi /CD43 hi ). The development of beneficial tumor-infiltrating NK cells of DLI-origin required host CD4 + T cell help in part by producing IL2, as well as by limiting regulatory CD4 + T cells (Tregs). IL2 blockade impaired the NK-dependent melanoma control, which could not be rescued by IL2 administration beyond CD4 + T cell help. Our findings linked NK allograft acceptance-CD4 + 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.

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