NK cell-mediated recruitment of dendritic cells to the tumor negatively impacts on anti-tumor CD8 T-cell priming

RAFFO IRAOLAGOITÍA, XIMENA LUCÍA; SPALLANZANI, RAÚL GERMÁN; TORRES, NICOLÁS IGNACIO; ZIBLAT, ANDREA; DOMAICA, CAROLINA INÉS; ZWIRNER, NORBERTO WALTER; FUERTES, MERCEDES BEATRIZ

Mar del Plata

Congreso; 62a Reunión Anual de la Sociedad Argentina de Inmunología; 2014

Sociedad Argentina de Inmunología

Spontaneous T cell priming can occur in response to a growing tumor and the presence of activated CD8 T cells has positive prognostic value. However, the innate immune mechanisms that regulate the adaptive antitumor immune responses remain ill-defined. NK cells are the first line of defense against tumors and can secrete cytokines and chemokines. However, a role of NK cells in dendritic cell (DC) recruitment to tumor microenvironment has not been pursued. Thus, the aim of this work was to study the NK cell-mediated DC recruitment and its impact on CD8 T-cell priming during the anti-tumor response. We performed transwell cell migration assays and we found that supernatants from tumor-primed NK cell recruited immature DCs (p<0.05), but not mature DCs, in a CCL3-dependent manner (p<0.05). Following subcutaneous implantation of MC57 fibrosarcoma cells in C57/B6 mice, we observed a reduced expression of CCL3 in tumors from NK cell-depleted mice compared to non-depleted mice (p<0.05). Moreover, we observed a positive correlation between the number of NK cells and DCs infiltrating the tumors (p<0.0001; Pearson r=0.92). However, we found that MHC class II and CD86 expression on DCs from tumor and tumor-draining lymph nodes (TDLN) and the number of DCs that have engulfed tumor antigens in TDLN was increased in NK cell-depleted mice (p<0.01; p<0.05). Consistently with this NK cell-regulatory role, we found that intratumoral NK cells expressed high-levels of PD-L1 (PD-L1hi) and that there was an increase in PD-L1hi NK cells in TDLN compared to naïve lymph nodes (p<0.05). Finally, using MC57 cells expressing the model antigen SIY we found an increased frequency of antigen-specific CD8 T cells and effector memory CD8 T cells  in NK cell-depleted mice (p<0.05). Our results describe a novel NK cell-dependent regulatory circuit that directly impacts on DC ability to prime an anti-tumor CD8 T cell response which may have implications on the development of anti-tumor immunotherapies.