Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop.
Cell
; 184(15): 3998-4015.e19, 2021 07 22.
Article
in En
| MEDLINE
| ID: mdl-34157302
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
T-Lymphocytes, Regulatory
/
Feedback, Physiological
/
CTLA-4 Antigen
/
Neoplasms
Type of study:
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell
Year:
2021
Document type:
Article