Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells
Beatrice Schuler-Thurner, Erwin S Schultz, Thomas G Berger, Georg Weinlich, Susanne Ebner, Petra Woerl, Armin Bender, Bernadette Feuerstein, Peter O Fritsch, Nikolaus Romani, Gerold Schuler, Beatrice Schuler-Thurner, Erwin S Schultz, Thomas G Berger, Georg Weinlich, Susanne Ebner, Petra Woerl, Armin Bender, Bernadette Feuerstein, Peter O Fritsch, Nikolaus Romani, Gerold Schuler
Abstract
There is consensus that an optimized cancer vaccine will have to induce not only CD8+ cytotoxic but also CD4+ T helper (Th) cells, particularly interferon (IFN)-gamma-producing, type 1 Th cells. The induction of strong, ex vivo detectable type 1 Th cell responses has not been reported to date. We demonstrate now that the subcutaneous injection of cryopreserved, mature, antigen-loaded, monocyte-derived dendritic cells (DCs) rapidly induces unequivocal Th1 responses (ex vivo detectable IFN-gamma-producing effectors as well as proliferating precursors) both to the control antigen KLH and to major histocompatibility complex (MHC) class II-restricted tumor peptides (melanoma-antigen [Mage]-3.DP4 and Mage-3.DR13) in the majority of 16 evaluable patients with metastatic melanoma. These Th1 cells recognized not only peptides, but also DCs loaded with Mage-3 protein, and in case of Mage-3DP4-specific Th1 cells IFN-gamma was released even after direct recognition of viable, Mage-3-expressing HLA-DP4+ melanoma cells. The capacity of DCs to rapidly induce Th1 cells should be valuable to evaluate whether Th1 cells are instrumental in targeting human cancer and chronic infections.
Figures
![Figure 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2193752/bin/012100f6a.jpg)
![Figure 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2193752/bin/012100f6b.jpg)
![Figure 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2193752/bin/012100f1.jpg)
![Figure 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2193752/bin/012100f2.jpg)
Figure 3.
Induction of tumor-specific Th1 effector…
Figure 3.
Induction of tumor-specific Th1 effector cells by DC immunization Mage-3.DP4 (a and c)…
Figure 3.
Induction of tumor-specific Th1 effector…
Figure 3.
Induction of tumor-specific Th1 effector cells by DC immunization Mage-3.DP4 (a and c)…
Figure 4.
Kinetics of tumor-specific Th1 effector…
Figure 4.
Kinetics of tumor-specific Th1 effector induction PBMCs of patients were serially tested every…
Figure 5.
Induction of tumor-specific recall Th…
Figure 5.
Induction of tumor-specific recall Th responses by DC immunization pre- and post therapy…
Figure 7.
Mage-3.DP4-specific Th clones recognize autologous…
Figure 7.
Mage-3.DP4-specific Th clones recognize autologous DCs that have processed Mage-3 protein and even…
- Functional analysis of tumor-specific Th cell responses detected in melanoma patients after dendritic cell-based immunotherapy.Schultz ES, Schuler-Thurner B, Stroobant V, Jenne L, Berger TG, Thielemanns K, van der Bruggen P, Schuler G. Schultz ES, et al. J Immunol. 2004 Jan 15;172(2):1304-10. doi: 10.4049/jimmunol.172.2.1304. J Immunol. 2004. PMID: 14707109
- Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients.de Vries IJ, Lesterhuis WJ, Scharenborg NM, Engelen LP, Ruiter DJ, Gerritsen MJ, Croockewit S, Britten CM, Torensma R, Adema GJ, Figdor CG, Punt CJ. de Vries IJ, et al. Clin Cancer Res. 2003 Nov 1;9(14):5091-100. Clin Cancer Res. 2003. PMID: 14613986
- A polyclonal anti-vaccine CD4 T cell response detected with HLA-DP4 multimers in a melanoma patient vaccinated with MAGE-3.DP4-peptide-pulsed dendritic cells.Zhang Y, Renkvist N, Sun Z, Schuler-Thurner B, Glaichenhaus N, Schuler G, Boon T, van der Bruggen P, Colau D. Zhang Y, et al. Eur J Immunol. 2005 Apr;35(4):1066-75. doi: 10.1002/eji.200425847. Eur J Immunol. 2005. PMID: 15756643
- Dendritic cell gene therapy.Onaitis M, Kalady MF, Pruitt S, Tyler DS. Onaitis M, et al. Surg Oncol Clin N Am. 2002 Jul;11(3):645-60. doi: 10.1016/s1055-3207(02)00027-3. Surg Oncol Clin N Am. 2002. PMID: 12487060 Review.
- Novel dendritic cell-based vaccination in late stage melanoma.Schneble EJ, Yu X, Wagner TE, Peoples GE. Schneble EJ, et al. Hum Vaccin Immunother. 2014;10(11):3132-8. doi: 10.4161/hv.29110. Hum Vaccin Immunother. 2014. PMID: 25483650 Free PMC article. Review.
- Emerging strategies in targeting tumor-resident myeloid cells for cancer immunotherapy.Wang Y, Johnson KCC, Gatti-Mays ME, Li Z. Wang Y, et al. J Hematol Oncol. 2022 Aug 28;15(1):118. doi: 10.1186/s13045-022-01335-y. J Hematol Oncol. 2022. PMID: 36031601 Free PMC article. Review.
- The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma.Donne R, Lujambio A. Donne R, et al. Hepatology. 2022 Aug 21:10.1002/hep.32740. doi: 10.1002/hep.32740. Online ahead of print. Hepatology. 2022. PMID: 35989535 Review.
- Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer.Lurje I, Hammerich L, Tacke F. Lurje I, et al. Int J Mol Sci. 2020 Oct 6;21(19):7378. doi: 10.3390/ijms21197378. Int J Mol Sci. 2020. PMID: 33036244 Free PMC article. Review.
- Dendritic Cells and Myeloid Derived Suppressor Cells Fully Responsive to Stimulation via Toll-Like Receptor 4 Are Rapidly Induced from Bone-Marrow Cells by Granulocyte-Macrophage Colony-Stimulating Factor.Kong YY, Wilson K, Apostolopoulos V, Plebanski M. Kong YY, et al. Vaccines (Basel). 2020 Sep 12;8(3):522. doi: 10.3390/vaccines8030522. Vaccines (Basel). 2020. PMID: 32932705 Free PMC article.
- Acute SARS-CoV-2 Infection Impairs Dendritic Cell and T Cell Responses.Zhou R, To KK, Wong YC, Liu L, Zhou B, Li X, Huang H, Mo Y, Luk TY, Lau TT, Yeung P, Chan WM, Wu AK, Lung KC, Tsang OT, Leung WS, Hung IF, Yuen KY, Chen Z. Zhou R, et al. Immunity. 2020 Oct 13;53(4):864-877.e5. doi: 10.1016/j.immuni.2020.07.026. Epub 2020 Aug 4. Immunity. 2020. PMID: 32791036 Free PMC article.
-
- Boon, T., P.G. Coulie, and B. van den Eynde. 1997. Tumor antigens recognized by T cells. Immunol. Today. 18:267–268. - PubMed
-
- Rosenberg, S.A. 1999. A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity. 10:281–287. - PubMed
-
- Pardoll, D.M., and S.L. Topalian. 1998. The role of CD4+ T cell responses in antitumor immunity. Curr. Opin. Immunol. 10:588–594. - PubMed
-
- Wang, R. 2001. The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity. Trends Immunol. 22:269–276. - PubMed
-
- Ada, G. 2001. Vaccines and vaccination. N. Engl. J. Med. 345:1042–1053. - PubMed
- Clinical Trial
- Research Support, Non-U.S. Gov't
- Adult
- Aged
- Antigens, Neoplasm*
- Cancer Vaccines / immunology*
- Cancer Vaccines / therapeutic use
- Cytotoxicity, Immunologic / immunology
- Dendritic Cells / immunology*
- Dendritic Cells / transplantation*
- Female
- Humans
- Immunologic Memory
- Interferon-gamma / metabolism
- Interleukin-2 / metabolism
- Interleukin-4 / metabolism
- Kinetics
- Male
- Melanoma / immunology*
- Melanoma / pathology
- Melanoma / therapy
- Middle Aged
- Neoplasm Metastasis / immunology*
- Neoplasm Metastasis / therapy
- Neoplasm Proteins / immunology*
- Th1 Cells / immunology*
- Vaccination
- Antigens, Neoplasm
- Cancer Vaccines
- Interleukin-2
- MAGEA3 protein, human
- Neoplasm Proteins
- Interleukin-4
- Interferon-gamma
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
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![Figure 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2193752/bin/012100f3ac.jpg)
Figure 3.
Induction of tumor-specific Th1 effector…
Figure 3.
Induction of tumor-specific Th1 effector cells by DC immunization Mage-3.DP4 (a and c)…
Figure 4.
Kinetics of tumor-specific Th1 effector…
Figure 4.
Kinetics of tumor-specific Th1 effector induction PBMCs of patients were serially tested every…
Figure 5.
Induction of tumor-specific recall Th…
Figure 5.
Induction of tumor-specific recall Th responses by DC immunization pre- and post therapy…
Figure 7.
Mage-3.DP4-specific Th clones recognize autologous…
Figure 7.
Mage-3.DP4-specific Th clones recognize autologous DCs that have processed Mage-3 protein and even…
- Functional analysis of tumor-specific Th cell responses detected in melanoma patients after dendritic cell-based immunotherapy.Schultz ES, Schuler-Thurner B, Stroobant V, Jenne L, Berger TG, Thielemanns K, van der Bruggen P, Schuler G. Schultz ES, et al. J Immunol. 2004 Jan 15;172(2):1304-10. doi: 10.4049/jimmunol.172.2.1304. J Immunol. 2004. PMID: 14707109
- Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients.de Vries IJ, Lesterhuis WJ, Scharenborg NM, Engelen LP, Ruiter DJ, Gerritsen MJ, Croockewit S, Britten CM, Torensma R, Adema GJ, Figdor CG, Punt CJ. de Vries IJ, et al. Clin Cancer Res. 2003 Nov 1;9(14):5091-100. Clin Cancer Res. 2003. PMID: 14613986
- A polyclonal anti-vaccine CD4 T cell response detected with HLA-DP4 multimers in a melanoma patient vaccinated with MAGE-3.DP4-peptide-pulsed dendritic cells.Zhang Y, Renkvist N, Sun Z, Schuler-Thurner B, Glaichenhaus N, Schuler G, Boon T, van der Bruggen P, Colau D. Zhang Y, et al. Eur J Immunol. 2005 Apr;35(4):1066-75. doi: 10.1002/eji.200425847. Eur J Immunol. 2005. PMID: 15756643
- Dendritic cell gene therapy.Onaitis M, Kalady MF, Pruitt S, Tyler DS. Onaitis M, et al. Surg Oncol Clin N Am. 2002 Jul;11(3):645-60. doi: 10.1016/s1055-3207(02)00027-3. Surg Oncol Clin N Am. 2002. PMID: 12487060 Review.
- Novel dendritic cell-based vaccination in late stage melanoma.Schneble EJ, Yu X, Wagner TE, Peoples GE. Schneble EJ, et al. Hum Vaccin Immunother. 2014;10(11):3132-8. doi: 10.4161/hv.29110. Hum Vaccin Immunother. 2014. PMID: 25483650 Free PMC article. Review.
- Emerging strategies in targeting tumor-resident myeloid cells for cancer immunotherapy.Wang Y, Johnson KCC, Gatti-Mays ME, Li Z. Wang Y, et al. J Hematol Oncol. 2022 Aug 28;15(1):118. doi: 10.1186/s13045-022-01335-y. J Hematol Oncol. 2022. PMID: 36031601 Free PMC article. Review.
- The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma.Donne R, Lujambio A. Donne R, et al. Hepatology. 2022 Aug 21:10.1002/hep.32740. doi: 10.1002/hep.32740. Online ahead of print. Hepatology. 2022. PMID: 35989535 Review.
- Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer.Lurje I, Hammerich L, Tacke F. Lurje I, et al. Int J Mol Sci. 2020 Oct 6;21(19):7378. doi: 10.3390/ijms21197378. Int J Mol Sci. 2020. PMID: 33036244 Free PMC article. Review.
- Dendritic Cells and Myeloid Derived Suppressor Cells Fully Responsive to Stimulation via Toll-Like Receptor 4 Are Rapidly Induced from Bone-Marrow Cells by Granulocyte-Macrophage Colony-Stimulating Factor.Kong YY, Wilson K, Apostolopoulos V, Plebanski M. Kong YY, et al. Vaccines (Basel). 2020 Sep 12;8(3):522. doi: 10.3390/vaccines8030522. Vaccines (Basel). 2020. PMID: 32932705 Free PMC article.
- Acute SARS-CoV-2 Infection Impairs Dendritic Cell and T Cell Responses.Zhou R, To KK, Wong YC, Liu L, Zhou B, Li X, Huang H, Mo Y, Luk TY, Lau TT, Yeung P, Chan WM, Wu AK, Lung KC, Tsang OT, Leung WS, Hung IF, Yuen KY, Chen Z. Zhou R, et al. Immunity. 2020 Oct 13;53(4):864-877.e5. doi: 10.1016/j.immuni.2020.07.026. Epub 2020 Aug 4. Immunity. 2020. PMID: 32791036 Free PMC article.
-
- Boon, T., P.G. Coulie, and B. van den Eynde. 1997. Tumor antigens recognized by T cells. Immunol. Today. 18:267–268. - PubMed
-
- Rosenberg, S.A. 1999. A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity. 10:281–287. - PubMed
-
- Pardoll, D.M., and S.L. Topalian. 1998. The role of CD4+ T cell responses in antitumor immunity. Curr. Opin. Immunol. 10:588–594. - PubMed
-
- Wang, R. 2001. The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity. Trends Immunol. 22:269–276. - PubMed
-
- Ada, G. 2001. Vaccines and vaccination. N. Engl. J. Med. 345:1042–1053. - PubMed
- Clinical Trial
- Research Support, Non-U.S. Gov't
- Adult
- Aged
- Antigens, Neoplasm*
- Cancer Vaccines / immunology*
- Cancer Vaccines / therapeutic use
- Cytotoxicity, Immunologic / immunology
- Dendritic Cells / immunology*
- Dendritic Cells / transplantation*
- Female
- Humans
- Immunologic Memory
- Interferon-gamma / metabolism
- Interleukin-2 / metabolism
- Interleukin-4 / metabolism
- Kinetics
- Male
- Melanoma / immunology*
- Melanoma / pathology
- Melanoma / therapy
- Middle Aged
- Neoplasm Metastasis / immunology*
- Neoplasm Metastasis / therapy
- Neoplasm Proteins / immunology*
- Th1 Cells / immunology*
- Vaccination
- Antigens, Neoplasm
- Cancer Vaccines
- Interleukin-2
- MAGEA3 protein, human
- Neoplasm Proteins
- Interleukin-4
- Interferon-gamma
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
![Figure 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2193752/bin/012100f3bd.jpg)
Figure 4.
Kinetics of tumor-specific Th1 effector…
Figure 4.
Kinetics of tumor-specific Th1 effector induction PBMCs of patients were serially tested every…
Figure 5.
Induction of tumor-specific recall Th…
Figure 5.
Induction of tumor-specific recall Th responses by DC immunization pre- and post therapy…
Figure 7.
Mage-3.DP4-specific Th clones recognize autologous…
Figure 7.
Mage-3.DP4-specific Th clones recognize autologous DCs that have processed Mage-3 protein and even…
![Figure 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2193752/bin/012100f4.jpg)
![Figure 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2193752/bin/012100f5.jpg)
![Figure 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2193752/bin/012100f7.jpg)
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- Pardoll, D.M., and S.L. Topalian. 1998. The role of CD4+ T cell responses in antitumor immunity. Curr. Opin. Immunol. 10:588–594.
- Wang, R. 2001. The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity. Trends Immunol. 22:269–276.
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Source: PubMed