Recruitment of dendritic cells to tumor microenvironment mediated by NK cell derived chemotactic factors

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

Los Cocos

Congreso; 61a Reunión Anual de la Sociedad Argentina de Inmunología; 2013

Sociedad Argentina de Inmunología

Contrary to preconceptions, spontaneous T cell priming occurs frequently in response to a growing tumor. It has recently been reported that antitumor CD8+ T cell priming is dependent on dendritic cells (DC), however the innate immune mechanisms that promote their recruitment to tumors remain ill-defined. We have previously reported that Natural Killer (NK) cells constitute a critical component for the antitumor immune response since antigen-specific CD8+ T cell priming was severely reduced in NK cell-depleted mice compared to non-depleted mice. Although NK cells can produce chemokines upon cytokine stimulation, a role of NK cells in DC recruitment has not been pursued. Therefore, the aim of this work was to study if NK cells can induce the migration of DC to tumors, in vitro and in vivo. To address this, C57BL/6 mice were subcutaneously challenged with MC57 fibrosarcoma cells and the tumor infiltrating immune cells were studied at early stages by flow cytometry. We observed an early DC (CD3-B220-CD11c+) and NK cell (DX5+CD3-) infiltration followed by CD8+ T cells. NK cell-depleted mice showed a significant decrease in DC tumor infiltration compared to control mice six days after tumor challenge (p<0.05). Moreover, we observed a positive correlation between the number of NK cells and activated DCs (CD3-B220-CD11c+CD86+) infiltrating the tumors (p<0.001; r=0.87). In order to determine if tumor-activated NK cells are able to attract DCs in vitro, supernatants from isolated NK cells co-cultured with MC57 cells were tested for their chemotactic activity towards bone marrow-derived DCs (BMDCs) in a transwell cell migration assay. While robust chemoattractive activity for BMDCs was detected in the supernatants of co-cultures, no similar activity was detectable in the supernatants of resting NK cells or MC57 cells cultured alone (p<0.05). Our results suggest that NK cells can recruit DCs to the tumor microenvironment, enhancing the spontaneous antitumor T cell priming.