Intratumor OX40 stimulation inhibits IRF1 expression and IL-10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Alessia Burocchi, Paola Pittoni, Andrea Gorzanelli, Mario P. Colombo, Silvia Piconese

Research output: Contribution to journalArticle

Abstract

Treg cells maintain the tumor microenvironment in an immunosuppressive state preventing an effective anti-tumor immune response. A possible strategy to overcome Treg-cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while being induced in activated effector T cells. OX40 stimulation, by the agonist mAb OX86, inhibits Treg-cell suppression and boosts effector T-cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, the most abundant CD4 + populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor interferon regulatory factor 1 (IRF1). Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to DCs. The CD40L/CD40 axis was required for Tem-cell-mediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg-cell suppression and enhancement of the Tem-cell adjuvant effect both concurred to free DCs from immunosuppression and activate the immune response against the tumor.

Original languageEnglish
Pages (from-to)3615-3626
Number of pages12
JournalEuropean Journal of Immunology
Volume41
Issue number12
DOIs
Publication statusPublished - Dec 2011

Fingerprint

Interferon Regulatory Factor-1
CD40 Ligand
Regulatory T-Lymphocytes
Interleukin-10
T-Lymphocytes
Neoplasms
Tumor Microenvironment
Licensure
Therapeutics
Immunosuppressive Agents
Immunosuppression
Transcription Factors
Population

Keywords

  • CD40L
  • IL-10
  • OX40
  • T effector memory cells
  • Treg cells

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Intratumor OX40 stimulation inhibits IRF1 expression and IL-10 production by Treg cells while enhancing CD40L expression by effector memory T cells. / Burocchi, Alessia; Pittoni, Paola; Gorzanelli, Andrea; Colombo, Mario P.; Piconese, Silvia.

In: European Journal of Immunology, Vol. 41, No. 12, 12.2011, p. 3615-3626.

Research output: Contribution to journalArticle

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