Regulatory T cells and treatment of cancer

doi:10.1016/j.coi.2008.04.008

Current Opinion in Immunology

Volume 20, Issue 2, April 2008, Pages 241-246

https://doi.org/10.1016/j.coi.2008.04.008 Get rights and content

CD4+CD25+FOXP3+ regulatory T cells (Tregs) are elevated in cancers and can thwart protective antitumor immunity. Recent human cancer trials suggest that depleting Tregs can be clinically beneficial. Additional types of deleterious regulatory cells are also increased in cancer. Tregs also play unanticipated roles in cancer therapy in that some drugs unexpectedly increase (e.g. cancer vaccines or IL-2 treatment) or decrease (e.g. antineoangiogenesis agents or receptor tyrosine kinase inhibitors) their numbers or function. Managing deleterious effects of regulatory cells represents a novel and potentially effective way to give immunotherapy for cancer. New insights into molecular mechanisms governing trafficking, differentiation, and function of these cells suggest novel approaches to manipulating them as treatment strategies.

Introduction

This commentary examines the enormous increases in knowledge regarding dysfunctional regulatory cells in cancer, primarily citing work appearing in the past three years. Older works are acknowledged in existing comprehensive reviews. This commentary focuses on CD4+CD25+FOXP3+ regulatory T cells (Tregs). It is not meant to be an exhaustive review of tumor Tregs, which are treated in excellent reviews such as [1]. Tregs inhibit otherwise protective antitumor immunity and predict reduced survival in cancer [1]. Important developments in the understanding of Treg differentiation and accumulation in tumors will be discussed with respect to using such knowledge therapeutically.

Current cancer immunotherapies capitalize on infectious disease concepts that might not apply to malignancies [2]. Recent work demonstrates that reversing deleterious immune dysfunction makes active interventions such as vaccines more effective in cancer [3]. Much experimental, and emerging clinical data suggest that managing deleterious Treg effects are important components of these novel anticancer immune strategies [4].

Regulatory cells other than CD4+CD25+FOXP3+ Tregs have also been recently described in cancer [1, 2, 3, 4]. Their relative contributions to immune dysfunction, and the clinical consequences of interfering with their function remain to be defined, but offer many additional approaches to treatment.

Section snippets

Background

Malignant tumors pose special challenges to immunity. On the one hand, their abnormalities should target them for immune destruction. On the other hand, they are self. Thus, protective mechanisms against autoimmunity could impede antitumor immunity.

Peripheral self-tolerance is mediated by CD4+CD25+ Tregs. However, activated effector T cells express the identical CD4+CD25+ phenotype, and thus Tregs cannot be distinguished by surface phenotype alone. FOXP3 was recently identified as essential to

Vaccines

It is well known that vaccines induce antigen-specific effector cells. Tregs are also antigen-specific cells, but until recently their possible generation in active immunization was unstudied. We now know that vaccines induce tumor-specific Tregs in mice [31]. A cervical cancer vaccine induced CD4+CD25+FOXP3+ cells in humans [32], but function and specificity were not assessed. Means to generate antigen-specific effector cells while limiting generation of antigen-specific Tregs is crucial to

Conclusions

Tumors employ myriad mechanisms to defeat host immunity. Many such mechanisms ultimately induce functional tumor CD4+CD25+FOXP3+ Treg accumulation. Reducing Treg function in patients with cancer should allow more effective immune-based therapies, alone or in combination with other therapies. Recent insights into mechanisms of Treg differentiation, trafficking and suppressive function suggest novel means to manage deleterious Treg effects. Treg management is a better general term than Treg

Acknowledgements

I thank my laboratory group members for their invaluable help and my many colleagues whose work could not be cited here owing to space limitations. Supported by FD003118, CA105207, CA100425, CA054174, the Fanny Rippel Foundation and the CTRC Foundation.

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Regulatory T cells and treatment of cancer

Introduction

Section snippets

Background

Vaccines

Conclusions

Acknowledgements

J Immunol

Blood

J Surg Res

J Exp Med

Blood

Immunol Rev

Clin Cancer Res

J Immunol

Nat Med

Nat Med

Eur J Haematol

Regulatory T cells, tumour immunity and immunotherapy

Nat Rev Immunol

Tregs and rethinking cancer immunotherapy

J Clin Invest

Immunosuppressive networks in the tumour environment and their therapeutic relevance

Nat Rev Cancer

Manipulating T Regulatory Cells in Cancer Immunotherapy

Exp Rev Derm

Regulatory T-cell development: is Foxp3 the decider?

Nat Med

Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10

Cancer Immunol Immunother

A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment

Clin Cancer Res

Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance

J Immunol

Neuropilin-1 expression identifies a subset of regulatory T cells in human lymph nodes that is modulated by preoperative chemoradiation therapy in cervical cancer

Immunology

CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ Treg cells

J Exp Med

Enhanced functionality of CD4+CD25highFoxP3+ regulatory T cells in the peripheral blood of patients with prostate cancer

Clin Cancer Res

Expansion of human T regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma

Cancer Res

CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells

Blood

The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma

Proc Natl Acad Sci U S A

Human ovarian carcinoma cells generate CD4(+)CD25(+) regulatory T cells from peripheral CD4(+)CD25(−) T cells through secreting TGF-beta

Cancer Lett

Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25− into CD25+ T regulatory cells

Blood

Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase

J Clin Invest

Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma

Clin Cancer Res

Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma

Haematologica

Small numbers of residual tumor cells at the site of primary inoculation are critical for anti-tumor immunity following challenge at a secondary location

Cancer Immunol Immunother

Localisation pattern of Foxp3(+) regulatory T cells is associated with clinical behaviour in gastric cancer

Br J Cancer

The ratio of FOXP3+ regulatory T cells to granzyme B+ cytotoxic T/NK cells predicts prognosis in classical Hodgkin lymphoma and is independent of bcl-2 and MAL expression

Am J Clin Pathol

Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma

Carcinogenesis