NK cells are known to kill tumor cells and produce proinflammatory cytokines that lead to the generation of tumor-specific CTLs. Many studies have used MHC class I-deficient tumor cells and/or adjuvants that induce NK cell responses. In this study, the focus was on less-immunogenic lymphoma cells that express MHC class I as a model to study NK cell responses to tumors that do not directly stimulate NK cell activation. When RMA tumor cells that expressed a truncated version of OVA, or RMA cells alone, were injected into mice that were depleted of NK cells, the mice developed an increased number of tumor-specific CTLs, increased IFN-γ responses, and a higher amount of Ag presentation in draining LNs compared with mice with intact NK cells. These data suggest that NK cells can inhibit the development of effective adaptive immunity in the absence of signals that trigger NK cell activation.

DCs are critical in initiating immune responses by cross-priming of tumor antigens to T cells. Previous results showed that NK cells inhibited DC-mediated cross-presentation of tumor Ags both in vivo and in vitro. In this study, enhanced Ag presentation was observed in draining lymph nodes in TRAIL−/− and DR5−/− mice compared to that of wild-type mice. NK cells inhibit DC cross-priming of tumor antigens in vitro, but not direct presentation of endogenous antigens. NK cells lacking TRAIL but not perforin were not able to inhibit DC cross-priming of tumor Ags. DCs that lack expression of TRAIL receptor DR5 were less susceptible to NK cell-mediated inhibition of cross-priming and cross-linking of DR5 receptor led to reduced generation of MHC class I-antigen peptide complex, followed by attenuated cross-priming of CD8+ T cells. In addition, key molecules involved in the TRAIL/DR5 pathway during DC/NK cell interactions were determined. In summary, these data indicate a novel alternative pathway for DC/NK cell interactions in anti-tumor immunity and may reflect homeostasis of both DCs and NK cells for regulation of CD8+ T cell function in physiological conditions.

These data demonstrate that the effectiveness of inhibitory receptor blockade depends upon the tissue location of the tumor cells.