T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy

Aida S. Hansen; Lea S. Jensen; Kristine R. Gammelgaard; Kristoffer G. Ryttersgaard; Christian Krapp; Jesper Just; Kasper L. Jønsson; Pia B. Jensen; Thomas Boesen; Mogens Johannsen; Anders Etzerodt; Bent W. Deleuran; Martin R. Jakobsen

doi:10.1002/jev2.12350

T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy

Aida S. Hansen^*, Lea S. Jensen, Kristine R. Gammelgaard, Kristoffer G. Ryttersgaard, Christian Krapp, Jesper Just, Kasper L. Jønsson, Pia B. Jensen, Thomas Boesen, Mogens Johannsen, Anders Etzerodt, Bent W. Deleuran, Martin R. Jakobsen^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

12 Citations (Scopus)

Abstract

A key phenomenon in cancer is the establishment of a highly immunosuppressive tumour microenvironment (TME). Despite advances in immunotherapy, where the purpose is to induce tumour recognition and hence hereof tumour eradication, the majority of patients applicable for such treatment still fail to respond. It has been suggested that high immunological activity in the tumour is essential for achieving effective response to immunotherapy, which therefore have led to exploration of strategies that triggers inflammatory pathways. Here activation of the stimulator of interferon genes (STING) signalling pathway has been considered an attractive target, as it is a potent trigger of pro-inflammatory cytokines and types I and III interferons. However, immunotherapy combined with targeted STING agonists has not yielded sustained clinical remission in humans. This suggests a need for exploring novel adjuvants to improve the innate immunological efficacy. Here, we demonstrate that extracellular vesicles (EVs), derived from activated CD4⁺ T cells (T-EVs), sensitizes macrophages to elevate STING activation, mediated by IFNγ carried on the T-EVs. Our work support that T-EVs can disrupt the immune suppressive environment in the tumour by reprogramming macrophages to a pro-inflammatory phenotype, and priming them for a robust immune response towards STING activation.

Original language	English
Article number	12350
Journal	Journal of Extracellular Vesicles
Volume	12
Issue	8
Number of pages	17
ISSN	2001-3078
DOIs	https://doi.org/10.1002/jev2.12350
Publication status	Published - Aug 2023

Keywords

cancer immunology
CDN therapy
extracellular vesicles
IFNγ
macrophages
STING
T cells
Neoplasms/metabolism
T-Lymphocytes
Humans
Macrophages/metabolism
Tumor Microenvironment
Extracellular Vesicles/metabolism
Interferons/genetics
Immunotherapy

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Hansen, A. S., Jensen, L. S., Gammelgaard, K. R., Ryttersgaard, K. G., Krapp, C., Just, J., Jønsson, K. L., Jensen, P. B., Boesen, T., Johannsen, M., Etzerodt, A., Deleuran, B. W., & Jakobsen, M. R. (2023). T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy. Journal of Extracellular Vesicles, 12(8), Article 12350. https://doi.org/10.1002/jev2.12350

@article{53555eb318ee4e34af1fb0d871f4041f,

title = "T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy",

abstract = "A key phenomenon in cancer is the establishment of a highly immunosuppressive tumour microenvironment (TME). Despite advances in immunotherapy, where the purpose is to induce tumour recognition and hence hereof tumour eradication, the majority of patients applicable for such treatment still fail to respond. It has been suggested that high immunological activity in the tumour is essential for achieving effective response to immunotherapy, which therefore have led to exploration of strategies that triggers inflammatory pathways. Here activation of the stimulator of interferon genes (STING) signalling pathway has been considered an attractive target, as it is a potent trigger of pro-inflammatory cytokines and types I and III interferons. However, immunotherapy combined with targeted STING agonists has not yielded sustained clinical remission in humans. This suggests a need for exploring novel adjuvants to improve the innate immunological efficacy. Here, we demonstrate that extracellular vesicles (EVs), derived from activated CD4+ T cells (T-EVs), sensitizes macrophages to elevate STING activation, mediated by IFNγ carried on the T-EVs. Our work support that T-EVs can disrupt the immune suppressive environment in the tumour by reprogramming macrophages to a pro-inflammatory phenotype, and priming them for a robust immune response towards STING activation.",

keywords = "cancer immunology, CDN therapy, extracellular vesicles, IFNγ, macrophages, STING, T cells, Neoplasms/metabolism, T-Lymphocytes, Humans, Macrophages/metabolism, Tumor Microenvironment, Extracellular Vesicles/metabolism, Interferons/genetics, Immunotherapy",

author = "Hansen, {Aida S.} and Jensen, {Lea S.} and Gammelgaard, {Kristine R.} and Ryttersgaard, {Kristoffer G.} and Christian Krapp and Jesper Just and J{\o}nsson, {Kasper L.} and Jensen, {Pia B.} and Thomas Boesen and Mogens Johannsen and Anders Etzerodt and Deleuran, {Bent W.} and Jakobsen, {Martin R.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.",

year = "2023",

month = aug,

doi = "10.1002/jev2.12350",

language = "English",

volume = "12",

journal = "Journal of Extracellular Vesicles",

issn = "2001-3078",

publisher = "Co-Action Publishing",

number = "8",

}

Hansen, AS, Jensen, LS, Gammelgaard, KR, Ryttersgaard, KG, Krapp, C, Just, J, Jønsson, KL, Jensen, PB , Boesen, T , Johannsen, M , Etzerodt, A , Deleuran, BW & Jakobsen, MR 2023, 'T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy', Journal of Extracellular Vesicles, vol. 12, no. 8, 12350. https://doi.org/10.1002/jev2.12350

T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy. / Hansen, Aida S.; Jensen, Lea S.; Gammelgaard, Kristine R. et al.
In: Journal of Extracellular Vesicles, Vol. 12, No. 8, 12350, 08.2023.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy

AU - Hansen, Aida S.

AU - Jensen, Lea S.

AU - Gammelgaard, Kristine R.

AU - Ryttersgaard, Kristoffer G.

AU - Krapp, Christian

AU - Just, Jesper

AU - Jønsson, Kasper L.

AU - Jensen, Pia B.

AU - Boesen, Thomas

AU - Johannsen, Mogens

AU - Etzerodt, Anders

AU - Deleuran, Bent W.

AU - Jakobsen, Martin R.

PY - 2023/8

Y1 - 2023/8

N2 - A key phenomenon in cancer is the establishment of a highly immunosuppressive tumour microenvironment (TME). Despite advances in immunotherapy, where the purpose is to induce tumour recognition and hence hereof tumour eradication, the majority of patients applicable for such treatment still fail to respond. It has been suggested that high immunological activity in the tumour is essential for achieving effective response to immunotherapy, which therefore have led to exploration of strategies that triggers inflammatory pathways. Here activation of the stimulator of interferon genes (STING) signalling pathway has been considered an attractive target, as it is a potent trigger of pro-inflammatory cytokines and types I and III interferons. However, immunotherapy combined with targeted STING agonists has not yielded sustained clinical remission in humans. This suggests a need for exploring novel adjuvants to improve the innate immunological efficacy. Here, we demonstrate that extracellular vesicles (EVs), derived from activated CD4+ T cells (T-EVs), sensitizes macrophages to elevate STING activation, mediated by IFNγ carried on the T-EVs. Our work support that T-EVs can disrupt the immune suppressive environment in the tumour by reprogramming macrophages to a pro-inflammatory phenotype, and priming them for a robust immune response towards STING activation.

AB - A key phenomenon in cancer is the establishment of a highly immunosuppressive tumour microenvironment (TME). Despite advances in immunotherapy, where the purpose is to induce tumour recognition and hence hereof tumour eradication, the majority of patients applicable for such treatment still fail to respond. It has been suggested that high immunological activity in the tumour is essential for achieving effective response to immunotherapy, which therefore have led to exploration of strategies that triggers inflammatory pathways. Here activation of the stimulator of interferon genes (STING) signalling pathway has been considered an attractive target, as it is a potent trigger of pro-inflammatory cytokines and types I and III interferons. However, immunotherapy combined with targeted STING agonists has not yielded sustained clinical remission in humans. This suggests a need for exploring novel adjuvants to improve the innate immunological efficacy. Here, we demonstrate that extracellular vesicles (EVs), derived from activated CD4+ T cells (T-EVs), sensitizes macrophages to elevate STING activation, mediated by IFNγ carried on the T-EVs. Our work support that T-EVs can disrupt the immune suppressive environment in the tumour by reprogramming macrophages to a pro-inflammatory phenotype, and priming them for a robust immune response towards STING activation.

KW - cancer immunology

KW - CDN therapy

KW - extracellular vesicles

KW - IFNγ

KW - macrophages

KW - STING

KW - T cells

KW - Neoplasms/metabolism

KW - T-Lymphocytes

KW - Humans

KW - Macrophages/metabolism

KW - Tumor Microenvironment

KW - Extracellular Vesicles/metabolism

KW - Interferons/genetics

KW - Immunotherapy

UR - http://www.scopus.com/inward/record.url?scp=85166329053&partnerID=8YFLogxK

U2 - 10.1002/jev2.12350

DO - 10.1002/jev2.12350

M3 - Journal article

C2 - 37525396

AN - SCOPUS:85166329053

SN - 2001-3078

VL - 12

JO - Journal of Extracellular Vesicles

JF - Journal of Extracellular Vesicles

IS - 8

M1 - 12350

ER -

T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy

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