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. 2002 Jan 22;99(2):931-6.
doi: 10.1073/pnas.022634999. Epub 2002 Jan 15.

Tumor lysate-pulsed dendritic cells can elicit an effective antitumor immune response during early lymphoid recovery

W Asavaroengchai  1 , Y Kotera, J J Mulé
Affiliations

Tumor lysate-pulsed dendritic cells can elicit an effective antitumor immune response during early lymphoid recovery

W Asavaroengchai et al. Proc Natl Acad Sci U S A. .

Abstract

Dendritic cells (DC) can serve to immunize the newborn immune system to foreign antigen. In a lymphopenic environment, naive T cells undergoing homeostasis-driven proliferation can acquire increased sensitivity to antigen stimulation. Here, we evaluated the capacity of DC to effectively prime the host immune system to elicit antitumor effects in the setting of early lymphoid reconstitution after bone marrow transplantation (BMT). Indeed, bone marrow-derived, cytokine-driven DC pulsed with whole tumor lysates (TP-DC) could, early on, prime a specific and long-lasting antitumor immune response, which mediated the rejection of a lethal challenge of a weakly immunogenic breast tumor. In the therapeutic setting, TP-DC could also inhibit the growth of preexisting breast tumor metastases by repetitive immunizations initiated early after BMT. Spleen T cells obtained from mice immunized with TP-DC early after BMT showed a substantial increase in tumor-specific IFN-gamma production. Our findings demonstrate that it is possible to promote effective antitumor immunity in a defined lymphopenic environment through DC-based immunization.

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Figures

Figure 1
Figure 1
Confocal microscopy reveals efficient DC phagocytosis of MT-901 tumor cell lysates. DC and tumor cell lysates are shown labeled with red (PKH-26 dye) and green (PKH-2 dye) fluorescence, respectively. Yellow fluorescence represents overlap of both dyes. DC were analyzed 4 h after the addition of lysates.
Figure 2
Figure 2
TP-DC immunization can inhibit MT-901 breast tumor growth when initiated on day 7 post-BMT. NT mice received BMT alone. TP-DC mice were immunized twice weekly starting on day 0 or 7 post-BMT. At 4 weeks post-BMT, mice were inoculated s.c. with 3 × 105 viable MT-901 tumor cells. Data are reported as the average tumor area ± SEM (P < 0.01). Data represent the combination of three separate experiments.
Figure 3
Figure 3
Repetitive TP-DC immunization can prevent MT-901 breast tumor growth and elicit specific IFN-γ-producing immune cells when initiated early post-BMT. (A) TP-DC groups were immunized thrice weekly starting on day 7 post-BMT. Immunized and control mice were challenged with two different doses of viable MT-901 tumor cells at 4 weeks post-BMT. Data are reported as the average tumor size ± SEM of five mice per group and are representative of two experiments (P < 0.01). (B) Tumor-specific IFN-γ production in BMT mice immunized with MT-901 TP-DC. Spleens were harvested 7 days after the third vaccine injection. Responder spleen cells (NT or TP-DC) were cultured with either irradiated MT-901 or A20 irrelevant tumor. After 48 h, culture supernatants were collected and the amount of IFN-γ was measured by standard ELISA method. Data are reported in pg/ml (mean ± SEM of triplicate samples) and are representative of two experiments (P < 0.03).
Figure 4
Figure 4
TP-DC immunization can induce tumor-specific protective immunity following BMT. BMT mice were either left untreated (NT), or were immunized thrice weekly with either MT-901 tumor lysates alone or with MT-901 TP-DC starting on day 7 post-BMT. All mice were then challenged s.c. with viable tumor cells at 4 weeks post-BMT. Mice received 3 × 105 MT-901 cells in one flank and irrelevant 1 × 105 A20 cells in the opposite flank. Data are reported as the average tumor size ± SEM of five mice per group. A representative experiment of two is shown (P < 0.01).
Figure 5
Figure 5
TP-DC immunization can protect BMT mice from pulmonary metastases formation. Both BMT and normal, non-BMT mice were either left untreated or were immunized as described in the legends to Figs. 3 and 4. All mice then were challenged i.v. with 2 × 105 viable MT-901 tumor cells. Data are reported as mean number of metastases ± SEM of five mice per group at day 7 postchallenge. A representative experiment of three is shown (P < 0.01).
Figure 6
Figure 6
Regression of established pulmonary metastases by TP-DC immunization of BMT mice. Mice were inoculated with 3 × 105 MT-901 tumor cells i.v. Seven days later, mice were left untreated or received BMT as described in Materials and Methods. TP-DC group was immunized thrice, starting 7 days post-BMT. Data are reported as mean number of metastases ± SEM of five mice per group at 7 days after three immunizations. No BMT vs. BMT alone, P < 0.05; BMT alone vs. TP-DC, P < 0.01. A representative of three experiments is shown.
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