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

Cell. 2021 Jul 22;184(15):3998-4015.e19. doi: 10.1016/j.cell.2021.05.027. | PubMed

Francesco Marangoni¹, Ademi Zhakyp², Michela Corsini³, Shannon N Geels⁴, Esteban Carrizosa², Martin Thelen³, Vinidhra Mani², Jasper N Prüßmann², Ross D Warner³, Aleksandra J Ozga², Mauro Di Pilato², Shivashankar Othy⁴, Thorsten R Mempel⁵

1. The Center for Immunology and Inflammatory Diseases (CIID), Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: f.marangoni@uci.edu.
2. The Center for Immunology and Inflammatory Diseases (CIID), Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
3. The Center for Immunology and Inflammatory Diseases (CIID), Massachusetts General Hospital, Boston, MA 02114, USA.
4. Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA.
5. The Center for Immunology and Inflammatory Diseases (CIID), Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: tmempel@mgh.harvard.edu.

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.

Presented By Francesco Marangoni | ORCID iD