Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines.

Abstract

SummaryAntigen presentation by host dendritic cells (DC) is critical for the initiation of adaptive immune responses. We have previously demonstrated in immunogenic routine tumor models that bone marrow (BM)-derived DC pulsed ex vivo with synthetic tumor-associated peptides, naturally expressed by tumor cells, serve as effective antitumor vaccines, protecting animals against an otherwise lethal tumor challenge (Mayordomo, J. I., T. Zorina, W.J. Storkus, C. Celluzzi, L. D. Falo, C.J. Melief, T. lldstad, W. M. Kast, A. B. DeLeo, and M. T. . Nature Med. 1:1297-1302. However, T cell-defined epitopes have not been identified for most human cancers. To explore the utility of this approach in the treatment of tumors expressing as yet uncharacterized epitopes, syngeneic granulocyte/macrophage colony-stimulating factorstimulated and BM-derived DC, pulsed with unfractionated acid-eluted tumor peptides (Storkus, W. J., H.J. Zeh III, R. D. Salter, and M. T. Lotze. 1993.J. lmmunother. 14:94-103) were used to treat mice bearing spontaneous, established tumors. The adoptive transfer of 5 3( 105 tumor peptide-pulsed DC dramatically suppressed the growth ofweaHy immunogenic tumors in day 4 to day 8 established MCA205 (H-2 b) and TS/A (H-2 a) tumor models, when applied in three biweeHy intravenous injections. Using the immunogenic C3 (H-2 b) tumor model in B6 mice, tumor peptide-pulsed DC therapy resulted in the erradication of established d14 tumors and long-term survival in 100% of treated animals. The DC-driven antitumor immune response was primarily cell mediated since the transfer of spleen cells, but not sera, from immunized mice efficiently protected sublethally irradiated naive mice against a subsequent tumor challenge. Furthermore, depletion of either CD4 + or CD8 + T cells from tumor-bearing mice before therapy totally suppressed the therapeutic efficacy of DC pulsed with tumor-derived peptides. Costimulation of the host cell-mediated antitumor immunity was critical since inoculation of the chimeric fusion protein CTLA4-Ig virtually abrogated the therapeutic effects of peptide-pulsed DC in vivo. The analysis of the cytokine pattern in the draining lymph nodes and spleens of tumor-bearing mice immunized with DC pulsed with tumor-eluted peptides revealed a marked upregulation of interleukin (IL) 4 and interferon (IFN) ~/ production, as compared with mice immunized with DC alone or DC pulsed with irrelevant peptides. DCinduced antitumor effects were completely blocked by coadministration of neutralizing monoclonal antibody directed against T helper cell 1-associated cytokines (such as IL-12, tumor necrosis factor or, IFN-~/), and eventually, but not initially, blocked by anti-raiL-4 mAb. Based on these results, we believe that DC pulsed with acid-eluted peptides derived from autologous tumors represents a novel approach to the treatment of established, weaHy imnmnogenic tumors, and serves as a basis for designing clinical trials in cancer patients.R ecent advances in the understanding of antigen presentation, antigen reco...

Co-delivery of T helper 1-biasing cytokine genes enhances the efficacy of gene gun immunization of mice: studies with the model tumor antigen β-galactosidase and the BALB/c Meth A p53 tumor-specific antigen

“…9,10 However, a powerful Th1-and CTLmediated response with production of IFN-␥ is thought to be necessary for the induction of antitumor immunity. 11 Whereas the two types of responses should be distinguishable based on the relative intensities of the cellular immune reactivity they induce, the strong immunogenicity of the foreign Ag used in the model studies tends to obscure these differences. They can be distinguished, however, on the basis of the isotype profile of the Ag-specific antibodies involved in the responses.…”

Intratumoral injection of immature dendritic cells enhances antitumor effect of hyperthermia using magnetic nanoparticles

“…To date, several methods for induction of antitumor immunity by DCs have been investigated. The major methods for antigen loading into DCs are pulsing DCs with proteins or peptides extracted from tumor cells, [26][27][28] transfecting DCs with gene encoding tumor antigens, 29 fusing DCs with tumor cells 30,31 or culturing DCs with tumor cells. 32 Although some of these methods require primary culture of tumor cells from patients, primary cultures often fail to give the required number of cells, or expanded tumor cells often show different antigens from those expressed in tumor specimens due to changes in immunological characteristics over the long culture period for expansion.…”

Induction of tumour-specific CD8+ cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer

“…Unfortunately, the possible immunization of cancer patients using defined tumour antigens is limited at present to a handful of human tumour types in which candidates for tumour rejection antigens have been identified. In an attempt to overcome these major limitations, several investigators have recently reported induction of effective tumour immunity using DCs pulsed with unfractionated tumour-derived materials, acid eluted peptides or messenger RNA (mRNA) (Boczkowski et al, 1996;Nair et al, 1997a,b;Zitvogel et al, 1996). Hence, DC vaccine treatment might be extended to patients with a variety of solid tumours, provided that in vitro confirmation of tumourspecific CTL activity has been achieved.…”

“…Therefore, an alternative strategy for effective vaccination of tumour patients may be the use of unfractionated tumour-derived antigens such as whole tumour cells, peptides or proteins isolated from tumour cells. In this regard, effective tumour immunity in several murine tumour models has been induced using professional antigen presenting cells (pAPC) such as dendritic cells (DC) pulsed with unfractionated tumour-derived antigens in the form of peptides (Nair et al, 1997a;Zitvogel et al, 1996), cell sonicates (Nair et al, 1997b), or messenger RNA (mRNA) (Boczkowski et al, 1996).…”