Marangoni, Francesco, Zhakyp, Ademi, Corsini, Michela, Geels, Shannon N., Carrizosa, Esteban, Thelen, Martin ORCID: 0000-0002-2785-9726, Mani, Vinidhra, Pruessmann, Jasper N., Warner, Ross D., Ozga, Aleksandra J., Di Pilato, Mauro, Othy, Shivashankar and Mempel, Thorsten R. (2021). Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop. Cell, 184 (15). S. 3998 - 4035. CAMBRIDGE: CELL PRESS. ISSN 1097-4172

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Abstract

Foxp3(+) T regulatory (Treg) cells promote immunological tumor tolerance, but how their immune-suppressive function is regulated in the tumor microenvironment (TME) remains unknown. Here, we used intravital microscopy to characterize the cellular interactions that provide tumor-infiltrating Treg cells with critical activation signals. We found that the polyclonal Treg cell repertoire is pre-enriched to recognize antigens presented by tumor-associated conventional dendritic cells (cDCs). Unstable cDC contacts sufficed to sustain Treg cell function, whereas T helper cells were activated during stable interactions. Contact instability resulted from CTLA-4-dependent downregulation of co-stimulatory B7-family proteins on cDCs, mediated by Treg cells themselves. CTLA-4-blockade triggered CD28-dependent Treg cell hyper-proliferation in the TME, and concomitant Treg cell inactivation was required to achieve tumor rejection. Therefore, Treg cells self-regulate through a CTLA-4- and CD28-dependent feedback loop that adjusts their population size to the amount of local co-stimulation. Its disruption through CTLA-4-blockade may off-set therapeutic benefits in cancer patients.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Marangoni, FrancescoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhakyp, AdemiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Corsini, MichelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geels, Shannon N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carrizosa, EstebanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thelen, MartinUNSPECIFIEDorcid.org/0000-0002-2785-9726UNSPECIFIED
Mani, VinidhraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pruessmann, Jasper N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warner, Ross D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozga, Aleksandra J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Di Pilato, MauroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Othy, ShivashankarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mempel, Thorsten R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-597235
DOI: 10.1016/j.cell.2021.05.027
Journal or Publication Title: Cell
Volume: 184
Number: 15
Page Range: S. 3998 - 4035
Date: 2021
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4172
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
REGULATORY T-CELLS; DENDRITIC CELLS; IMMUNOLOGICAL SYNAPSE; ANTITUMOR-ACTIVITY; PD-1 BLOCKADE; CTLA-4; HOMEOSTASIS; DEPLETION; RESPONSES; ACTIVATIONMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59723

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