NK cells lose their ability to control MHC-I-deficient tumor cells outside circulation.

A common tumor immune-evasion mechanism is downregulation of major histocompatibility complex Class-I (MHC-I) that enables malignant cell escape from cytotoxic T-cell responses. This strategy also contributes to nonresponsiveness of tumors to T-cell targeted immune-checkpoint blockade. MHC-I is an antigen-presenting molecule that also functions as an inhibitory ligand for natural killer (NK) cells. Thus, loss of MHC-I should render cells susceptible to NK cell-mediated cytotoxicity. However, this does not always occur. Previously it was demonstrated that NK cells were able to strongly reject MHC-I-deficient bone marrow cells in the circulation, yet they failed to reject MHC-I-deficient organ grafts, suggesting restricted NK cell cytotoxicity in tissues. We hypothesized that a similar NK cell tolerance to MHC-I-deficient cells occurs in the context of solid cancers. We compared NK cell recruitment and activation using WT and MHC-I-deficient B16F10 melanoma models. We demonstrated that NK cells eradicate circulating MHC-I−/− B16F10 cells, effectively preventing tumor metastasis to the lungs. In contrast, NK cells failed to clear MHC-I−/− B16F10 tumors when implanted subcutaneously, nor was the growth of these tumors affected by NK cell depletion. Interestingly, spontaneous lymph node (LN) metastasis from MHC-I-deficient solid tumors was fully abrogated in an NK cell-dependent manner, indicating functional inhibition of NK cells in peripheral tissues, but not in circulation or draining lymphatics. In conclusion, we demonstrate NK cell tolerance to MHC-I-deficient tumor cells in tissues, but not in circulation, which suggests the presence of non-MHC-I NK cell-inhibitory signals in solid organs. Our research uncovers a fundamental aspect of NK cell biology and will open up the possibility of new NK cell-based therapeutic strategies to control solid tumors that escape cytotoxic CD8+ T-cell responses by downregulating MHC-I. Citation Format: Marta Requesens, Mark Bunting, Maulik Vyas, Shawn Demehri. NK cells lose their ability to control MHC-I-deficient tumor cells outside circulation [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B87.