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

Affiliations

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.

PMID: 34157302
100 References
9 citations

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.

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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Biomimetic and Materials-Potentiated Cell Engineering for Cancer Immunotherapy. Tingting Zhang, Yushan Yang, +6 authors, Yongyong Li. less Pharmaceutics, 2022 Apr 24; 14(4). PMID: 35456568 Free PMC article. Review.
Landscape of helper and regulatory antitumour CD4+ T cells in melanoma. Giacomo Oliveira, Kari Stromhaug, +24 authors, Catherine J Wu. less Nature, 2022 May 05; 605(7910). PMID: 35508657
Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets. Yan Tie, Fan Tang, Yu-Quan Wei, Xia-Wei Wei. J Hematol Oncol, 2022 May 19; 15(1). PMID: 35585567 Free PMC article. Review.

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