Dendritic Cell-Induced Activation of Adaptive and Innate Antitumor Immunity

Abstract

While studying Ag-pulsed syngeneic dendritic cell (DC) immunization, we discovered that surprisingly, unpulsed DCs induced protection against tumor lung metastases resulting from i.v. injection of a syngeneic BALB/c colon carcinoma CT26 or a syngeneic C57BL/6 lung carcinoma LL/2. Splenocytes or immature splenic DCs did not protect. The protection was mediated by NK cells, in that it was abrogated by treatment with anti-asialo-GM1 but not anti-CD8, and was induced by CD1−/− DCs unable to stimulate NKT cells, but did not occur in beige mice lacking NK cells. Protection correlated with increased NK activity, and increased infiltration of NK but not CD8+ cells in lungs of tumor-bearing mice. Protection depended on the presence of costimulatory molecules CD80, CD86, and CD40 on the DCs, but surprisingly did not require DCs that could make IL-12 or IL-15. Unexpectedly, protection sensitive to anti-asialo-GM1 and increased NK activity were still present 14 mo after DC injection. As NK cells lack memory, we found by depletion that CD4+ not CD8+ T cells were required for induction of the NK antitumor response. The role of DCs and CD4+ T cells provides a novel mechanism for NK cell induction and innate immunity against cancer that may have potential in preventing clinical metastases.

NK Cells Are Required for Dendritic Cell–Based Immunotherapy at the Time of Tumor Challenge

“…The DC-based immunotherapy was optimized by providing a potent microbial stimulus of whole bacteria and our results confirm those of others showing that NK cells and IFN-g are required for optimal DC based therapy (17,18,23).…”

“…3B). In contrast, some studies have demonstrated that immunization with syngenic DC alone (in the absence of tumor Ag) can induce NK cell-dependent antitumor responses against melanoma, colon, or lung carcinoma (17,20,23). We have previously noted that immunization with syngenic DC in the absence of tumor Ag can induce antimelanoma immunity in the prophylactic setting, but only if FCS Ags are present in both the DC and the melanoma culture medium (37,39).…”

“…NK cells detect and destroy malignant and virally infected cells (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Aside from their cytotoxic abilities against low MHC-I tumor cells, interactions between NK cells and DC have been shown to result in the activation of a helper NK cell phenotype, characterized by the production of IFN-g and associated with enhanced CTL and Th1 responses (15,16,(25)(26)(27)(28)(29).…”

“…Adjusting DC-based therapies to augment NK cell function and IFN-g secretion could therefore complement current CD8 T cell strategies in controlling tumor growth (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

DC therapy induces long‐term NK reactivity to tumors via host DC

“…For prolonged periods (up to 12 months), the immunized mice have NKT and NK cells that are in a ''primed'' state, being able to produce IFN-g rapidly upon challenge with B16 melanoma and to resist the metastases of B16 to the lung. After we had performed our experiments, we became aware of two publications that reported long-term NK-based resistance induced by DC vaccines [12,13]. Our paper extends this prior research in three ways: (i) by comparing DC Figure 5.…”