Abstract
Dendritic cells (DCs) are highly effective antigen-presenting cells that, when derived from cancer patients, seem to be functionally deficient. Herein, we show that vaccination with allogeneic DC–autologous tumor cell hybrids affects the phenotype and improves the function of monocyte-derived DCs (Mo-DCs) from cancer patients. Mononuclear cells were isolated from patients’ peripheral blood by density gradient centrifugation, and adherent cells were cultured in medium containing GM-CSF plus IL-4 and, after 5 days, TNF-α. After 2 more days, Mo-DCs were harvested and their CD80, CD86, and CD83 expression was assessed by flow cytometry. They were also used as stimulators in mixed lymphocyte reactions (MLR), where IFN-γ production was measured by ELISA. Mo-DCs from unvaccinated patients expressed significantly lower levels of CD86, and tended to express lower levels of CD83 than Mo-DCs from healthy donors. However, Mo-DCs generated after hybrid cell vaccination presented increased expression of the same markers and induced significantly higher levels of IFN-γ in MLR. These results indicate that the use of allogeneic DC–based cancer vaccines induces recovery of DC function in metastatic cancer patients and, therefore, could precede the use of autologous DCs for vaccine preparation. Such an approach could be relevant and should be investigated in clinical trials.
Similar content being viewed by others
References
Allavena P, Piemonti L, Longoni D, Bernasconi S, Stoppacciaro A, Ruco L, Mantovani A (1998) IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages. Eur J Immunol 28:359–369
Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Puledran B, Palucka K (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811
Barbuto JAM, Ensina LF, Neves AR, Bergami-Santos PC, Marques R, Leite KRM, Camara-Lopes LH, Buzaid AC (2002) Dendritic-tumor hybrid cell therapeutic vaccination for metastatic melanoma and renal cell carcinoma patients. International symposium on predictive oncology and intervention strategies, Paris, France, 9--12 February 2002. http://www.cancerprev.org/Journal/Issues/26/101/1011/4579 Cited 24 August 2004
Bedrosian I, Mick R, Xu S, Nisenbaum H, Faries M, Zhang P, Cohen PA, Koski G, Czerniecki BJ (2003) Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J Clin Oncol 21:3826–3835
Brossart P, Wirths S, Brugger, Kanz L (2001) Dendritic cells in cancer vaccines. J Exp Hematol 29:1247–1255
Caux C, Dezutter-Dambuyant C, Schmitt D, Banchereau J (1992) GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature 360:258–261
Caux C, Vanbervliet B, Massacrier C, Azuma M, Okumura K, Lanier LL, Banchereau J (1994) B70/B7-2 is identical to CD86 and is the major functional ligand for CD28 expressed on human dendritic cells. J Exp Med 180:1841–1877
Chaux P, Moutet M, Faivre J, Martin F, Martin M (1996) Inflammatory cells infiltrating human colorectal carcinomas express HLA class II but not B7-1 and B7-2 costimulatory molecules of the T-cell activation. Lab Invest 74:975–983
Della Bella S, Gennaro M, Vaccari M, Ferraris C, Nicola S, Riva A, Clerici M, Greco M, Villa ML (2003) Altered maturation of peripheral blood dendritic cells in patients with breast cancer. Br J Cancer 89:1463–1472
Di Nico M, Emo RM (2000) Dendritic cells: specialized antigen presenting cells. Haematologica 85:202–207
Fields PE, Finch RJ, Gray GS, Zollner R, Thomas JL, Sturmhoefel K, Lee K, Wolf S, Gajewski TF, Fitch FW (1998) B7.1 is a quantitatively stronger costimulus than B7.2 in the activation of naive CD8+ TCR-transgenic T cells. J Immunol 161:5268–5275
Gabrilovich DI, Corak J, Ciernik IF, Kavanaugh D, Carbone DP (1997) Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res 3:483-490
Godelaine D, Carrasco J, Lucas S, Karanikas V, Schuler-Thurner B, Coulie PG, Schuler G, Boon T, Van Pel A (2003) Polyclonal CTL responses observed in melanoma patients vaccinated with dendritic cells pulsed with a MAGE-3.A1 peptide. J Immunol 171:4893–4897
Hasebe H, Nagayama H, Sato K, Enomoto M, Takeda Y, Takahashi TA, Hasumi K, Eriguchi M (2000) Dysfunctional regulation of the development of monocyte-derived dendritic cell in cancer patients. Biomed Pharmacother 54:291–298
Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, Engleman EG, Levy R (1996) Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 2:52–58
Ishida T, Oyama T, Carbone D, Gabrilovich DI (1998) Defective function of Langerhans cells in tumor-bearing animals is the result of defective maturation from hematopoietic progenitors. J Immunol 161:4842–4851
Kim J, Modlin RL, Moy RL, Dubinett SM, McHugh T, Nickoloff BJ, Uyemura K (1995) IL-10 production in cutaneous basal and squamous cell carcinomas: a mechanism for evading the local T cell immune response. J Immunol 155:2240–2247
Lang TJ, Nguyen P, Peach R, Gause WC, Via CS (2002) In vivo CD86 blockade inhibits CD4+ T cell activation, whereas CD80 blockade potentiates CD8+ T cell activation and CTL effector function. J Immunol 168:3786–3792
Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R (1994) Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1:793–801
Martin-Fontecha A, Moro M, Crosti MC, Veglia F, Casorati G, Dellabona P (2000) Vaccination with mouse mammary adenocarcinoma cells coexpressing B7-1 (CD80) and B7-2 (CD86) discloses the dominant effect of B7-1 in the induction of antitumor immunity. J Immunol 164:698–704
Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D (1998) Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 4:328–332
Orsini E, Guarini A, Chiaretti S, Mauro FR, Foa R (2003) The circulating dendritic cell compartment in patients with chronic lymphocytic leukemia is severely defective and unable to stimulate an effective T-cell response. Cancer Res 63:4497–4450
Piemonti L, Monti P, Zerbi A, Balzano G, Allavena P, Di Carlo V (2000) Generation and functional characterisation of dendritic cells from patients with pancreatic carcinoma with special regard to clinical applicability. Cancer Immunol Immunother 49:544-550
Romani N, Reider D, Heuer M, Ebner S, Kampgen E, Eibl B, Niederwieser D, Schuler G (1996) Generation of mature dendritic cells from human blood: an improved method with special regard to clinical applicability. J Immunol Methods 196:137–151
Slavik JM, Hutchcroft JE, Bierer BE (1999) CD28/CTLA-4 and CD80/CD86 families: signaling and function. Immunol Res 19:1–24
Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH (1997) Induction of tolerance by IL-10-treated dendritic cells. J Immunol 159:4772–4780
Thurner B, Roder C, Cieckmann D, Heuer M, Kruse M, Glaser A, Keikavoussi P, Kampgen E, Bender A, Schuler G (1999) Generation of large numbers of fully mature and stable dendritic cells from leukapheresis products for clinical application. J Immunol Methods 223:1–15
Trefzer U, Walden P (2003) Hybrid-cell vaccines for cancer immune therapy. Mol Biotechnol 25:63–69
Trefzer U, Weingart G, Chen Y, Herberth G, Adrian K, Winter H, Audring H, Guo Y, Sterry W, Walden P (2000) Hybrid cell vaccination for cancer immune therapy: first clinical trial with metastatic melanoma. Int J Cancer 85:618–626
Vasilevko V, Ghochikyan A, Holterman MJ, Agadjanyan MG (2002) CD80 (B7-1) and CD86 (B7-2) are functionally equivalent in the initiation and maintenance of CD4+ T-cell proliferation after activation with suboptimal doses of PHA. DNA Cell Biol 21:137–149
Young MR, Wright MA, Vellody K, Lathers DM (1999) Skewed differentiation of bone marrow CD34+ cells of tumor bearers from dendritic toward monocytic cells, and the redirection of differentiation toward dendritic cells by 1alpha,25-dihydroxyvitamin D3. Int J Immunopharmacol 21:675–688
Zhou L, Tedder TF (1996) CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells. Proc Natl Acad Sci U S A 93:2588–2592
Acknowledgements
This work was supported by FAPESP, grants no. 01-02339-8 and no. 01-07751-4 and by Capes.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Neves, A.R., Ensina, L.F.C., Anselmo, L.B. et al. Dendritic cells derived from metastatic cancer patients vaccinated with allogeneic dendritic cell–autologous tumor cell hybrids express more CD86 and induce higher levels of interferon-gamma in mixed lymphocyte reactions. Cancer Immunol Immunother 54, 61–66 (2005). https://doi.org/10.1007/s00262-004-0550-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-004-0550-8