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. 2012 May 1;1(3):326-333.
doi: 10.4161/onci.18852.

Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer

Helene Pere  1 , Corinne Tanchot, Jagadeesh Bayry, Magali Terme, Julien Taieb, Cecile Badoual, Olivier Adotevi, Nathalie Merillon, Elie Marcheteau, Ve Ronique Quillien, Claire Banissi, Alain Carpentier, Federico Sandoval, Mevyn Nizard, Françoise Quintin-Colonna, Guido Kroemer, Wolf H Fridman, Laurence Zitvogel, Ste Phane Oudard, Eric Tartour
Affiliations

Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer

Helene Pere et al. Oncoimmunology. .

Abstract

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) have emerged as a dominant T cell population inhibiting anti-tumor effector T cells. Initial strategies used for Treg-depletion (cyclophosphamide, anti-CD25 mAb…) also targeted activated T cells, as they share many phenotypic markers. Current, ameliorated approaches to inhibit Treg aim to either block their function or their migration to lymph nodes and the tumor microenvironment. Various drugs originally developed for other therapeutic indications (anti-angiogenic molecules, tyrosine kinase inhibitors,etc) have recently been discovered to inhibit Treg. These approaches are expected to be rapidly translated to clinical applications for therapeutic use in combination with immunomodulators.

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Figures

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Figure 1. Mechanisms of regulatory T cell inhibition (A) Secretion of immunosuppressive cytokines (IL-10, IL-35 and TGFβ) inhibiting effector T cells. (B) Cytolysis of effector T cells by production of Granzyme A and/or B. (C) Metabolic disruption of effector T cells by IL-2 deprivation. IL-2 is captured by CD25 expressed by Treg. (D) Inhibition of DC maturation by contact-dependent mechanisms (CTLA-4, CD80-CD86 interaction, Lag3/CMHII interaction) and effector function by IDO secretion.
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Figure 2. Recruitment, proliferation and induction of Treg in the tumor microenvironment. (i) Recruitment of CCR4+ activated Treg by a CCL22 gradient produced by the tumor. (ii) Tumor expression of VEGF, IL-10 or TGFβ blocks DC maturation responsible for Treg induction and proliferation. (iii) TGFβ secreted by the tumor converts conventional CD4+T cells into regulatory T cells.
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