Journal Article
. 2021 Jun; 184(15):3998-4015.e19.
doi: 10.1016/j.cell.2021.05.027.

Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop

Francesco Marangoni 1 Ademi Zhakyp 2 Michela Corsini 3 Shannon N Geels 4 Esteban Carrizosa 2 Martin Thelen 3 Vinidhra Mani 2 Jasper N Prüßmann 2 Ross D Warner 3 Aleksandra J Ozga 2 Mauro Di Pilato 2 Shivashankar Othy 4 Thorsten R Mempel 5 
  • PMID: 34157302
  •     100 References
  •     9 citations


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.

Keywords: CD28; CTLA-4; MP-IVM; NFAT; T regulatory cell; Treg cell; cytotoxic T lymphocyte-associated protein 4; multiphoton intravital microscopy; nuclear factor of activated T cells; tumor tolerance.

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