| First Author | Marangoni F | Year | 2021 |
| Journal | Cell | Volume | 184 |
| Issue | 15 | Pages | 3998-4015.e19 |
| PubMed ID | 34157302 | Mgi Jnum | J:316912 |
| Mgi Id | MGI:6728425 | Doi | 10.1016/j.cell.2021.05.027 |
| Citation | Marangoni F, et al. (2021) Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop. Cell 184(15):3998-4015.e19 |
| abstractText | 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. |
