Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists

Tanja Lövgren; Dhifaf Sarhan; Iva Truxová; Bhavesh Choudhary; Roeltje Maas; Jeroen Melief; Maria Nyström; Ulrika Edbäck; Renee Vermeij; Gina Scurti; Michael Nishimura; Giuseppe Masucci; Alex Karlsson-Parra; Andreas Lundqvist; Lars Adamson; Rolf Kiessling

doi:10.1007/s00262-017-2029-4

Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists

Tanja Lövgren, Dhifaf Sarhan, Iva Truxová, Bhavesh Choudhary, Roeltje Maas, Jeroen Melief, Maria Nyström, Ulrika Edbäck, Renee Vermeij, Gina Scurti, Michael Nishimura, Giuseppe Masucci, Alex Karlsson-Parra, Andreas Lundqvist, Lars Adamson, Rolf Kiessling

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.

Original language	English (US)
Pages (from-to)	1333-1344
Number of pages	12
Journal	Cancer Immunology, Immunotherapy
Volume	66
Issue number	10
DOIs	https://doi.org/10.1007/s00262-017-2029-4
State	Published - Oct 1 2017
Externally published	Yes

Bibliographical note

Funding Information:
Conflict of interest R Kiessling is in the Scientific Advisory Board for the companies Immunicum AB, Idogen Inc, Glactone Pharma AB, and Clinical Laserthermia Systems AB, and has received compensation for arranging courses for Bristol Myers Squibb and a research grant from Moderna Therapeutics. A. Karlsson-Parra is employed by, and a shareholder of, Immunicum AB. All other authors declare that they have no conflicts of interest.

Funding Information:
Acknowledgements This work was supported by The Swedish Cancer Society (R. Kiessling; 2013/379), The Cancer Society in Stockholm and The King Gustaf V’s Jubilee Foundation (R. Kiessling; 144102), The Swedish Medical Research Council (R. Kiessling; 521-2013-4100), Stockholm City Council Project Grant (R. Kiessling; ALF Medicin 2015, 20140036), Knut and Alice Wallenberg Foundations (R. Kiessling), O.E och Edla Johanssons vetenskapliga stiftelse (T. Lövgren), Stiftelsen Längmanska kulturfonden (T. Lövgren), and the National Institutes of Health (M. Nishimura; NIH P01 CA154778 and NIH R01 CA10494). We thank A.M. Salazar (Oncovir, Inc.) for providing Hiltonol.

Funding Information:
This work was supported by The Swedish Cancer Society (R. Kiessling; 2013/379), The Cancer Society in Stockholm and The King Gustaf V?s Jubilee Foundation (R. Kiessling; 144102), The Swedish Medical Research Council (R. Kiessling; 521-2013-4100), Stockholm City Council Project Grant (R. Kiessling; ALF Medicin 2015, 20140036), Knut and Alice Wallenberg Foundations (R. Kiessling), O.E och Edla Johanssons vetenskapliga stiftelse (T. L?vgren), Stiftelsen L?ngmanska kulturfonden (T. L?vgren), and the National Institutes of Health (M. Nishimura; NIH P01 CA154778 and NIH R01 CA10494). We thank A.M. Salazar (Oncovir, Inc.) for providing Hiltonol. In part previously published in ?Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival,? September 16?19, 2015, New York, NY, USA. Title: ?Enhanced IL-12 production and T cell stimulation ability by dendritic cells matured in presence of GMP-grade Toll-like receptor ligands and IFN-?,? Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B071. R Kiessling is in the Scientific Advisory Board for the companies Immunicum AB, Idogen Inc, Glactone Pharma AB, and Clinical Laserthermia Systems AB, and has received compensation for arranging courses for Bristol Myers Squibb and a research grant from Moderna Therapeutics. A. Karlsson-Parra is employed by, and a shareholder of, Immunicum AB. All other authors declare that they have no conflicts of interest.

Publisher Copyright:
© 2017, The Author(s).

Keywords

Cancer
Dendritic cell-vaccine
IFNγ
LPS
Poly I:C
R848

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1007/s00262-017-2029-4

Find It

Find It at U of M Libraries

Cite this

Lövgren, T., Sarhan, D., Truxová, I., Choudhary, B., Maas, R., Melief, J., Nyström, M., Edbäck, U., Vermeij, R., Scurti, G., Nishimura, M., Masucci, G., Karlsson-Parra, A., Lundqvist, A., Adamson, L., & Kiessling, R. (2017). Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists. Cancer Immunology, Immunotherapy, 66(10), 1333-1344. https://doi.org/10.1007/s00262-017-2029-4

Lövgren, T, Sarhan, D, Truxová, I, Choudhary, B, Maas, R, Melief, J, Nyström, M, Edbäck, U, Vermeij, R, Scurti, G, Nishimura, M, Masucci, G, Karlsson-Parra, A, Lundqvist, A, Adamson, L & Kiessling, R 2017, 'Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists', Cancer Immunology, Immunotherapy, vol. 66, no. 10, pp. 1333-1344. https://doi.org/10.1007/s00262-017-2029-4

@article{92d40970188748d080a7252152c7b44d,

title = "Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists",

abstract = "Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.",

keywords = "Cancer, Dendritic cell-vaccine, IFNγ, LPS, Poly I:C, R848",

author = "Tanja L{\"o}vgren and Dhifaf Sarhan and Iva Truxov{\'a} and Bhavesh Choudhary and Roeltje Maas and Jeroen Melief and Maria Nystr{\"o}m and Ulrika Edb{\"a}ck and Renee Vermeij and Gina Scurti and Michael Nishimura and Giuseppe Masucci and Alex Karlsson-Parra and Andreas Lundqvist and Lars Adamson and Rolf Kiessling",

note = "Funding Information: Conflict of interest R Kiessling is in the Scientific Advisory Board for the companies Immunicum AB, Idogen Inc, Glactone Pharma AB, and Clinical Laserthermia Systems AB, and has received compensation for arranging courses for Bristol Myers Squibb and a research grant from Moderna Therapeutics. A. Karlsson-Parra is employed by, and a shareholder of, Immunicum AB. All other authors declare that they have no conflicts of interest. Funding Information: Acknowledgements This work was supported by The Swedish Cancer Society (R. Kiessling; 2013/379), The Cancer Society in Stockholm and The King Gustaf V{\textquoteright}s Jubilee Foundation (R. Kiessling; 144102), The Swedish Medical Research Council (R. Kiessling; 521-2013-4100), Stockholm City Council Project Grant (R. Kiessling; ALF Medicin 2015, 20140036), Knut and Alice Wallenberg Foundations (R. Kiessling), O.E och Edla Johanssons vetenskapliga stiftelse (T. L{\"o}vgren), Stiftelsen L{\"a}ngmanska kulturfonden (T. L{\"o}vgren), and the National Institutes of Health (M. Nishimura; NIH P01 CA154778 and NIH R01 CA10494). We thank A.M. Salazar (Oncovir, Inc.) for providing Hiltonol. Funding Information: This work was supported by The Swedish Cancer Society (R. Kiessling; 2013/379), The Cancer Society in Stockholm and The King Gustaf V?s Jubilee Foundation (R. Kiessling; 144102), The Swedish Medical Research Council (R. Kiessling; 521-2013-4100), Stockholm City Council Project Grant (R. Kiessling; ALF Medicin 2015, 20140036), Knut and Alice Wallenberg Foundations (R. Kiessling), O.E och Edla Johanssons vetenskapliga stiftelse (T. L?vgren), Stiftelsen L?ngmanska kulturfonden (T. L?vgren), and the National Institutes of Health (M. Nishimura; NIH P01 CA154778 and NIH R01 CA10494). We thank A.M. Salazar (Oncovir, Inc.) for providing Hiltonol. In part previously published in ?Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival,? September 16?19, 2015, New York, NY, USA. Title: ?Enhanced IL-12 production and T cell stimulation ability by dendritic cells matured in presence of GMP-grade Toll-like receptor ligands and IFN-?,? Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B071. R Kiessling is in the Scientific Advisory Board for the companies Immunicum AB, Idogen Inc, Glactone Pharma AB, and Clinical Laserthermia Systems AB, and has received compensation for arranging courses for Bristol Myers Squibb and a research grant from Moderna Therapeutics. A. Karlsson-Parra is employed by, and a shareholder of, Immunicum AB. All other authors declare that they have no conflicts of interest. Publisher Copyright: {\textcopyright} 2017, The Author(s).",

year = "2017",

month = oct,

day = "1",

doi = "10.1007/s00262-017-2029-4",

language = "English (US)",

volume = "66",

pages = "1333--1344",

journal = "Cancer Immunology and Immunotherapy",

issn = "0340-7004",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "10",

}

TY - JOUR

T1 - Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists

AU - Lövgren, Tanja

AU - Sarhan, Dhifaf

AU - Truxová, Iva

AU - Choudhary, Bhavesh

AU - Maas, Roeltje

AU - Melief, Jeroen

AU - Nyström, Maria

AU - Edbäck, Ulrika

AU - Vermeij, Renee

AU - Scurti, Gina

AU - Nishimura, Michael

AU - Masucci, Giuseppe

AU - Karlsson-Parra, Alex

AU - Lundqvist, Andreas

AU - Adamson, Lars

AU - Kiessling, Rolf

N1 - Funding Information: Conflict of interest R Kiessling is in the Scientific Advisory Board for the companies Immunicum AB, Idogen Inc, Glactone Pharma AB, and Clinical Laserthermia Systems AB, and has received compensation for arranging courses for Bristol Myers Squibb and a research grant from Moderna Therapeutics. A. Karlsson-Parra is employed by, and a shareholder of, Immunicum AB. All other authors declare that they have no conflicts of interest. Funding Information: Acknowledgements This work was supported by The Swedish Cancer Society (R. Kiessling; 2013/379), The Cancer Society in Stockholm and The King Gustaf V’s Jubilee Foundation (R. Kiessling; 144102), The Swedish Medical Research Council (R. Kiessling; 521-2013-4100), Stockholm City Council Project Grant (R. Kiessling; ALF Medicin 2015, 20140036), Knut and Alice Wallenberg Foundations (R. Kiessling), O.E och Edla Johanssons vetenskapliga stiftelse (T. Lövgren), Stiftelsen Längmanska kulturfonden (T. Lövgren), and the National Institutes of Health (M. Nishimura; NIH P01 CA154778 and NIH R01 CA10494). We thank A.M. Salazar (Oncovir, Inc.) for providing Hiltonol. Funding Information: This work was supported by The Swedish Cancer Society (R. Kiessling; 2013/379), The Cancer Society in Stockholm and The King Gustaf V?s Jubilee Foundation (R. Kiessling; 144102), The Swedish Medical Research Council (R. Kiessling; 521-2013-4100), Stockholm City Council Project Grant (R. Kiessling; ALF Medicin 2015, 20140036), Knut and Alice Wallenberg Foundations (R. Kiessling), O.E och Edla Johanssons vetenskapliga stiftelse (T. L?vgren), Stiftelsen L?ngmanska kulturfonden (T. L?vgren), and the National Institutes of Health (M. Nishimura; NIH P01 CA154778 and NIH R01 CA10494). We thank A.M. Salazar (Oncovir, Inc.) for providing Hiltonol. In part previously published in ?Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival,? September 16?19, 2015, New York, NY, USA. Title: ?Enhanced IL-12 production and T cell stimulation ability by dendritic cells matured in presence of GMP-grade Toll-like receptor ligands and IFN-?,? Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B071. R Kiessling is in the Scientific Advisory Board for the companies Immunicum AB, Idogen Inc, Glactone Pharma AB, and Clinical Laserthermia Systems AB, and has received compensation for arranging courses for Bristol Myers Squibb and a research grant from Moderna Therapeutics. A. Karlsson-Parra is employed by, and a shareholder of, Immunicum AB. All other authors declare that they have no conflicts of interest. Publisher Copyright: © 2017, The Author(s).

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.

AB - Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.

KW - Cancer

KW - Dendritic cell-vaccine

KW - IFNγ

KW - LPS

KW - Poly I:C

KW - R848

UR - http://www.scopus.com/inward/record.url?scp=85020681116&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020681116&partnerID=8YFLogxK

U2 - 10.1007/s00262-017-2029-4

DO - 10.1007/s00262-017-2029-4

M3 - Article

C2 - 28601925

AN - SCOPUS:85020681116

SN - 0340-7004

VL - 66

SP - 1333

EP - 1344

JO - Cancer Immunology and Immunotherapy

JF - Cancer Immunology and Immunotherapy

IS - 10

ER -

Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists

Abstract

Bibliographical note

Keywords

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this