Induction of tumor-specific acquired immunity against already established tumors by selective stimulation of innate DEC-205+ dendritic cells

Abstract

Two major distinct subsets of dendritic cells (DCs) are arranged to regulate our immune responses in vivo; 33D1+ and DEC-205+ DCs. Using anti-33D1-specific monoclonal antibody, 33D1+ DCs were successfully depleted from C57BL/6 mice. When 33D1+ DC-depleted mice were stimulated with LPS, serum IL-12, but not IL-10 secretion that may be mediated by the remaining DEC-205+ DCs was markedly enhanced, which may induce Th1 dominancy upon TLR signaling. The 33D1+ DC-depleted mice, implanted with syngeneic Hepa1-6 hepatoma or B16-F10 melanoma cells into the dermis, showed apparent inhibition of already established tumor growth in vivo when they were subcutaneously (sc) injected once or twice with LPS after tumor implantation. Moreover, the development of lung metastasis of B16-F10 melanoma cells injected intravenously was also suppressed when 33D1+ DC-deleted mice were stimulated twice with LPS in a similar manner, in which the actual cell number of NK1.1+CD3− NK cells in lung tissues was markedly increased. Furthermore, intraperitoneal (ip) administration of a very small amount of melphalan (l-phenylalanine mustard; l-PAM) (0.25 mg/kg) in LPS-stimulated 33D1+ DC-deleted mice helped to induce H-2Kb-restricted epitope-specific CD8+ cytotoxic T lymphocytes (CTLs) among tumor-infiltrating lymphocytes against already established syngeneic E.G7-OVA lymphoma. These findings indicate the importance and effectiveness of selective targeting of a specific subset of DCs, such as DEC-205+ DCs alone or with a very small amount of anticancer drugs to activate both CD8+ CTLs and NK effectors without externally added tumor antigen stimulation in vivo and provide a new direction for tumor immunotherapy.

Vaccination with filamentous bacteriophages targeting DEC‐205 induces DC maturation and potent anti‐tumor T‐cell responses in the absence of adjuvants

“…However, DCs may play a dual role either inducing adaptive immune response or maintaining tolerance [13,22,23]. In particular, targeting of DEC-205 is usually not associated with the induction of antigen-specific T cells and thus in previous works additional DC activation/ maturation compounds needed to be given as well [6][7][8][9][10][11][12]. In contrast, using the fd delivery system, we observed that DCs targeted by fdsc-aDEC produced IFN-a and IL-6, and acquired the phenotype of mature DCs in the absence of other stimuli.…”

“…As mentioned above, the induction of functional effector activity via antigen chemically coupled to the anti-DEC-205 was contingent upon the presence of additional DC activation/ maturation compounds such as agonistic antibody directed against CD40 or poly I:C [7][8][9][10][11][12]. However, the administration of these compounds may have far-reaching consequences.…”

“…The anti-DEC-205 mAb has been used to deliver antigens to DCs. While delivering DEC-205 targeted antigen in conjugation with DC activation/maturation agents (such as anti-CD40 mAb, poly I:C and LPS) has been reported to result in a potent immune response [6][7][8][9][10][11][12], targeting DEC-205 in the absence of such maturation signals has been described to result in T-cell tolerance [13][14][15]. The development of vaccines able to access DCs, thereby eliciting more efficient immune responses, is one of the aims of immune therapy starting from the recent past [16,17].…”

Suppression of murine tumour growth through CD8+ cytotoxic T lymphocytes via activated DEC‐205+ dendritic cells by sequential administration of α‐galactosylceramide in vivo

“…Additionally, as we recently demonstrated, the selective activation of the DEC‐205 + DC subset might activate tumour‐specific CD8 + CTLs without additional tumour–antigen stimulation in vivo 19, 25. In this study, we demonstrate for the first time that the sequential administration of α ‐GalCer every 48 hr might convert tolerogenic DCs within the tumour mass into immunogenic DEC‐205 + DCs, which have an enhanced expression of co‐stimulation molecules and a cross‐presenting capacity that might prime and activate naive T cells within the tumour mass.…”

Co-operation of Innate and Acquired Immunity for Controlling Tumor Cells

“…In addition, DCs will not usually become tumor cells and thus are unable to present tumor antigens in conjunction with their class I MHC, despite expressing suitable co-stimulation molecules for the elicitation of tumor-specific CD8 + CTLs. On the basis of our recent findings (Moriya et al, 2010), this chapter propose a new direction for the establishment of tumor immunotherapy to generate tumor-derived epitope-specific class I MHC molecule-restricted acquired CD8 + CTLs against tumors by selective activation of DEC-205 + DCs that have the ability to process and cross-present antigenic fragments from externally captured tumor-derived products via class I MHC as well as innate effectors such as NKT cells and  T cells through their CD1 molecules (Takahashi, 2010).…”