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Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation
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Published on: August 13, 2013

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Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion

Sarah K Whiteside1, Francis M Grant2, Giorgia Alvisi3

  • 1Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.

Science Immunology
|December 15, 2023
PubMed

Insights

Depleting regulatory T (Treg) cells to fight cancer can backfire. Conventional T (Tconv) cells gain suppressive abilities, hindering therapy. Targeting IL-10 signaling alongside Treg depletion may improve cancer immunotherapy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Immunotherapy

Background:

  • Regulatory T (Treg) cells maintain immune homeostasis but suppress anti-cancer immune responses.
  • Current Treg cell-targeted cancer immunotherapies show limited success due to poorly understood resistance mechanisms.

Purpose of the Study:

  • To investigate the mechanisms underlying therapeutic failure in Treg cell-targeted cancer immunotherapy.
  • To identify alternative immunosuppressive pathways activated upon Treg cell depletion.

Main Methods:

  • Mouse models of Treg cell-targeted immunotherapy.
  • Analysis of T cell populations, gene expression (transcriptional profiling), and suppressive function ex vivo.
  • Assessment of IL-10's role in immunosuppression and therapeutic efficacy.
  • In vivo studies involving conditional gene deletion (Il10) and antibody blockade of IL-10 signaling.

Main Results:

  • Depletion of Treg cells induced suppressive function in CD4+ Foxp3- conventional T (Tconv) cells.
  • Tumor-infiltrating Foxp3- Tconv cells adopted a Treg-like transcriptional profile and suppressed T cell activity.
  • CD4+ Tconv cells expressing C-C motif receptor 8 (CCR8) were identified as a key suppressive population in tumors.
  • CCR8+ Tconv cells expanded systemically and intratumorally upon Treg cell depletion, mediating IL-10-dependent immunosuppression.
  • Conditional deletion of IL-10 in T cells or IL-10 signaling blockade synergized with Treg cell depletion to enhance anti-tumor immunity.

Conclusions:

  • Conventional T cells can acquire immunosuppressive functions upon Treg cell depletion, representing a novel mechanism of therapeutic resistance.
  • CCR8+ Tconv cells are a critical mediator of this secondary immunosuppression.
  • Targeting IL-10 signaling in conjunction with Treg cell depletion offers a promising strategy to overcome treatment resistance in cancer immunotherapy.

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