Tumor endothelial cell up-regulation of IDO1 is an immunosuppressive feed-back mechanism that reduces the response to CD40-stimulating immunotherapy
(2020) In OncoImmunology 9(1).- Abstract
CD40-stimulating immunotherapy can elicit potent anti-tumor responses by activating dendritic cells and enhancing T-cell priming. Tumor vessels orchestrate T-cell recruitment during immune response, but the effect of CD40-stimulating immunotherapy on tumor endothelial cells has not been evaluated. Here, we have investigated how tumor endothelial cells transcriptionally respond to CD40-stimulating immunotherapy by isolating tumor endothelial cells from agonistic CD40 mAb- or isotype-treated mice bearing B16-F10 melanoma, and performing RNA-sequencing. Gene set enrichment analysis revealed that agonistic CD40 mAb therapy increased interferon (IFN)-related responses in tumor endothelial cells, including up-regulation of the... (More)
CD40-stimulating immunotherapy can elicit potent anti-tumor responses by activating dendritic cells and enhancing T-cell priming. Tumor vessels orchestrate T-cell recruitment during immune response, but the effect of CD40-stimulating immunotherapy on tumor endothelial cells has not been evaluated. Here, we have investigated how tumor endothelial cells transcriptionally respond to CD40-stimulating immunotherapy by isolating tumor endothelial cells from agonistic CD40 mAb- or isotype-treated mice bearing B16-F10 melanoma, and performing RNA-sequencing. Gene set enrichment analysis revealed that agonistic CD40 mAb therapy increased interferon (IFN)-related responses in tumor endothelial cells, including up-regulation of the immunosuppressive enzyme Indoleamine 2, 3-Dioxygenase 1 (IDO1). IDO1 was predominantly expressed in endothelial cells within the tumor microenvironment, and its expression in tumor endothelium was positively correlated to T-cell infiltration and to increased intratumoral expression of IFNγ. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Combining agonistic CD40 mAb therapy with the IDO1 inhibitor epacadostat delayed tumor growth in B16-F10 melanoma, associated with increased activation of tumor-infiltrating T-cells. Hereby, we show that the tumor endothelial cells up-regulate IDO1 upon CD40-stimulating immunotherapy in response to increased IFNγ-secretion by T-cells, revealing a novel immunosuppressive feedback mechanism whereby tumor vessels limit T-cell activation.
(Less)
- author
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- CD40, IDO1, immunotherapy, melanoma, tumor endothelial cells
- in
- OncoImmunology
- volume
- 9
- issue
- 1
- article number
- 1730538
- pages
- 14 pages
- publisher
- Taylor & Francis
- external identifiers
-
- scopus:85081356873
- pmid:32231867
- ISSN
- 2162-4011
- DOI
- 10.1080/2162402X.2020.1730538
- language
- English
- LU publication?
- no
- additional info
- Publisher Copyright: © 2020, © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.
- id
- 7256e605-d278-4614-81a7-837a9f393d0b
- date added to LUP
- 2025-02-12 12:24:20
- date last changed
- 2025-06-04 21:26:29
@article{7256e605-d278-4614-81a7-837a9f393d0b,
abstract = {{<p>CD40-stimulating immunotherapy can elicit potent anti-tumor responses by activating dendritic cells and enhancing T-cell priming. Tumor vessels orchestrate T-cell recruitment during immune response, but the effect of CD40-stimulating immunotherapy on tumor endothelial cells has not been evaluated. Here, we have investigated how tumor endothelial cells transcriptionally respond to CD40-stimulating immunotherapy by isolating tumor endothelial cells from agonistic CD40 mAb- or isotype-treated mice bearing B16-F10 melanoma, and performing RNA-sequencing. Gene set enrichment analysis revealed that agonistic CD40 mAb therapy increased interferon (IFN)-related responses in tumor endothelial cells, including up-regulation of the immunosuppressive enzyme Indoleamine 2, 3-Dioxygenase 1 (IDO1). IDO1 was predominantly expressed in endothelial cells within the tumor microenvironment, and its expression in tumor endothelium was positively correlated to T-cell infiltration and to increased intratumoral expression of IFNγ. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Combining agonistic CD40 mAb therapy with the IDO1 inhibitor epacadostat delayed tumor growth in B16-F10 melanoma, associated with increased activation of tumor-infiltrating T-cells. Hereby, we show that the tumor endothelial cells up-regulate IDO1 upon CD40-stimulating immunotherapy in response to increased IFNγ-secretion by T-cells, revealing a novel immunosuppressive feedback mechanism whereby tumor vessels limit T-cell activation.</p>}},
author = {{Georganaki, Maria and Ramachandran, Mohanraj and Tuit, Sander and Núñez, Nicolás Gonzalo and Karampatzakis, Alexandros and Fotaki, Grammatiki and van Hooren, Luuk and Huang, Hua and Lugano, Roberta and Ulas, Thomas and Kaunisto, Aura and Holland, Eric C. and Ellmark, Peter and Mangsbo, Sara M. and Schultze, Joachim and Essand, Magnus and Tugues, Sonia and Dimberg, Anna}},
issn = {{2162-4011}},
keywords = {{CD40; IDO1; immunotherapy; melanoma; tumor endothelial cells}},
language = {{eng}},
number = {{1}},
publisher = {{Taylor & Francis}},
series = {{OncoImmunology}},
title = {{Tumor endothelial cell up-regulation of IDO1 is an immunosuppressive feed-back mechanism that reduces the response to CD40-stimulating immunotherapy}},
url = {{http://dx.doi.org/10.1080/2162402X.2020.1730538}},
doi = {{10.1080/2162402X.2020.1730538}},
volume = {{9}},
year = {{2020}},
}