Elsevier

Current Opinion in Immunology

Volume 33, April 2015, Pages 101-111
Current Opinion in Immunology

The interplay of effector and regulatory T cells in cancer

https://doi.org/10.1016/j.coi.2015.02.003Get rights and content

Highlights

  • Regulatory T (Treg) cells suppress effector (Teff) cells to drive immunosuppression.

  • Immunosuppression requires that Teff cells provide cytokine support for Treg cells.

  • Teff cells depart from this supportive state under specific conditions of immune activation.

  • Complex Treg and Teff cell population dynamics drives bistable immune states.

  • Therapeutic activation of Teff cells may destabilize Treg cells to cause durable cancer regression.

Regulatory T (Treg) cells suppress effector T (Teff) cells and prevent immune-mediated rejection of cancer. Much less appreciated are mechanisms by which Teff cells antagonize Treg cells. Herein, we consider how complex reciprocal interactions between Teff and Treg cells shape their population dynamics within tumors. Under states of tolerance, including during tumor escape, suppressed Teff cells support Treg cell populations through antigen-dependent provision of interleukin (IL)-2. During immune activation, Teff cells can lose this supportive capacity and directly antagonize Treg cell populations to neutralize their immunosuppressive function. While this latter state is rarely achieved spontaneously within tumors, we propose that therapeutic induction of immune activation has the potential to stably disrupt immunosuppressive population states resulting in durable cancer regression.

Introduction

Growth of tumors in immunocompetent hosts is at odds with the powerful ability of the immune system to recognize and kill cancer cells. The cancer immunoediting hypothesis has been proposed as a conceptual framework to account for this behavior [1]. According to this hypothesis, tumor development is characterized by an initial ‘elimination’ phase, during which a majority of cancer cells are destroyed by various components of the immune system. This is followed by an ‘equilibrium’ phase, during which pressure from the immune system contributes to selection of tumor variants that give rise to an ‘escape’ phase characterized by evasion from immune control and unrestrained tumor growth. While selection of antigen-loss variants represents a mechanism of tumor escape and has been shown to contribute to growth of orthotopic tumors [1, 2], it fails to explain why established tumors continue to express immunogenic epitopes that are recognized by tumor-infiltrating lymphocytes and the efficacy of certain immune-based therapies for cancer [3, 4, 5, 6, 7••, 8]. Growth of tumors containing immunogenic epitopes is better explained through an understanding of the critical role of immunosuppression in promoting tumor escape [9, 10, 11, 12]. Here, we review recent advances in our understanding of tumor immunosuppression and consider how a complex interplay between Treg and Teff cell populations dictates the outcome of tumor-specific immune responses.

A major advance in our understanding of peripheral tolerance arose with the identification of a suppressive subset of CD4+ T cells, referred to as Treg cells, that express the high-affinity receptor for interleukin (IL)-2, IL-2Rα, and whose deficiency in neonatally thymectomized mice results in lethal inflammatory disease [13]. The similar inflammatory phenotype manifested in ‘Scurfy’ mice [14] was later attributed to a complete defect in Treg cell formation caused by an inactivating mutation within the gene encoding the transcription factor (TF) Forkhead box P3 (Foxp3). This resulted in identification of Foxp3 as a lineage specifying TF of Treg cells [15, 16, 17]. A broader network of TFs, including BACH2 [18••] and Foxo1 [19••, 20, 21], are required establish the full Treg cell transcriptional program. Humans lacking a functional Foxp3 locus develop a lethal immune-mediated disease (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome; IPEX) [22], while genetic polymorphisms within the BACH2 locus are associated with multiple autoimmune and allergic diseases [18••]. These findings provide evidence that Treg cells regulate immune function in humans.

A complex interplay between CD4+ Treg and Teff cells determines the outcome of immune reactions. Under homeostatic conditions, Treg cells promote peripheral tolerance primarily through direct or indirect suppression of CD4+ Foxp3 Teff cells. This is evidenced by the absence of inflammation in Cd4-deficient mice which lack both Treg and CD4+ Teff cell populations [23]. Treg cells also suppress Teff cell function within tumors (Figure 1). In murine tumor models, transient ablation of Treg cells results in activation of CD4+ or CD8+ Teff cells and rejection of solid tumors [24, 25, 26••, 27]. In human tumors, low Treg cell to Teff cell ratios are associated with favorable survival in ovarian cancer [28, 29], breast cancer [30], non-small cell lung carcinoma [31], hepatocellular carcinoma [32], renal cell carcinoma [33], pancreatic cancer [34], gastric cancer [35], cervical cancer [36] and colorectal carcinoma [37]. CD4+ and CD8+ Teff cells exert tumoricidal activity through multiple means that are reviewed extensively elsewhere [38, 39]. Thus, the balance between Treg and Teff cells dictates the outcome of tumor-specific immune responses (Figure 1). It is therefore important to understand factors that affect the population dynamics of Treg and Teff cells within tumors.

Section snippets

Population dynamics of Treg and Teff cells within tumors

The immunosuppressive function of Treg cells is at odds with the capacity of the immune system to mediate brisk and functional Teff cell responses against harmful pathogens in the context of acute infection. This implies that Treg cell suppressive capacity may be neutralized during infection to promote clearance of disease. Emerging evidence presents multiple mechanisms by which Teff cells antagonize the size and function of Treg cell populations not only during infection, but also during

The role of IL-2 signaling in Treg and Teff cell population dynamics

IL-2 was originally characterized as a lymphocyte growth factor in vitro and was considered to have immunostimulatory function [40, 41]. Subsequent characterization using gene-deficient mice led to the surprising finding that its non-redundant biological function in vivo is to restrain lethal inflammation [42, 43]. This is attributable to a non-redundant requirement for IL-2 in Treg cell survival [44, 45, 46]. IL-2-driven induction of the anti-apoptotic Bcl-2 family member Mcl-1 is critical for

Treg-mediated suppression of Teff cell populations

In states of tolerance, including during tumor escape, Treg cells block the proliferation, survival and function of Teff cells through multiple means. These have been extensively reviewed [71] and are depicted in Figure 3a. A subset of Foxp3+ Treg cells constitutively express IL-2Rα and sequestration of IL-2 by Treg cells is a component of their suppressive function [72, 73]. However, expansion of Teff cells and induction of lethal inflammation caused by Treg cell insufficiency can proceed in

Opportunities for therapeutic intervention

Reciprocal antagonism and feed-forward reinforcement contribute to the potential for two distinct immune states. First, an immunosuppressive state, which is established early during the escape phase of tumor development, is stabilized through provision of IL-2 support by suppressed Teff cells for Treg cells. Second, an activated immune state, in which unrestrained Teff cell differentiation is accompanied by withdrawal of cytokine support and direct antagonism of Treg cell populations to drive

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements and funding

The authors were supported by a generous gift from Li Jinyuan and the Tiens Charitable Foundation, the NIH-Center for Regenerative Medicine, the Milstein Family Foundation and by the Intramural Research Program of the National Cancer Institute (ZIA BC010763). R.R. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 105663/Z/14/Z). The authors thank Alan Hoofring and Ethan Tyler for their assistance with illustrations, and David

References (132)

  • G. Oldenhove et al.

    Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection

    Immunity

    (2009)
  • A.M. Thornton et al.

    CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production

    J Exp Med

    (1998)
  • K. Nakamura et al.

    Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta

    J Exp Med

    (2001)
  • J.C. Marie et al.

    Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor

    Immunity

    (2006)
  • D.C. Gondek et al.

    Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism

    J Immunol

    (2005)
  • R. Noy et al.

    Tumor-associated macrophages: from mechanisms to therapy

    Immunity

    (2014)
  • A. Laurence et al.

    STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease

    Immunity

    (2012)
  • S. Malchow et al.

    Aire-dependent thymic development of tumor-associated regulatory T cells

    Science

    (2013)
  • S.Z. Josefowicz et al.

    Extrathymically generated regulatory T cells control mucosal TH2 inflammation

    Nature

    (2012)
  • G. Zhou et al.

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

    J Immunol

    (2007)
  • G.P. Dunn et al.

    The three Es of cancer immunoediting

    Annu Rev Immunol

    (2004)
  • P. Dubey et al.

    The immunodominant antigen of an ultraviolet-induced regressor tumor is generated by a somatic point mutation in the DEAD box helicase p68

    J Exp Med

    (1997)
  • A. Gros et al.

    PD-1 identifies the patient-specific CD8(+) tumor-reactive repertoire infiltrating human tumors

    J Clin Invest

    (2014)
  • E. Tran et al.

    Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer

    Science

    (2014)
  • M.E. Dudley et al.

    Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes

    Science

    (2002)
  • F.S. Hodi et al.

    Improved survival with ipilimumab in patients with metastatic melanoma

    N Engl J Med

    (2010)
  • O. Hamid et al.

    Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma

    N Engl J Med

    (2013)
  • S.L. Topalian et al.

    Safety, activity, and immune correlates of anti-PD-1 antibody in cancer

    N Engl J Med

    (2012)
  • G.A. Rabinovich et al.

    Immunosuppressive strategies that are mediated by tumor cells

    Annu Rev Immunol

    (2007)
  • S.A. Quezada et al.

    Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication

    Immunol Rev

    (2011)
  • T.F. Gajewski et al.

    Innate and adaptive immune cells in the tumor microenvironment

    Nat Immunol

    (2013)
  • C.A. Klebanoff et al.

    Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

    Trends Immunol

    (2005)
  • V.L. Godfrey et al.

    Fatal lymphoreticular disease in the scurfy (sf) mouse requires T cells that mature in a sf thymic environment: potential model for thymic education

    Proc Natl Acad Sci U S A

    (1991)
  • S. Hori et al.

    Control of regulatory T cell development by the transcription factor Foxp3

    Science

    (2003)
  • R. Khattri et al.

    An essential role for Scurfin in CD4+CD25+ T regulatory cells

    Nat Immunol

    (2003)
  • J.D. Fontenot et al.

    Foxp3 programs the development and function of CD4+CD25+ regulatory T cells

    Nat Immunol

    (2003)
  • R. Roychoudhuri et al.

    BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis

    Nature

    (2013)
  • W. Ouyang et al.

    Novel Foxo1-dependent transcriptional programs control T(reg) cell function

    Nature

    (2012)
  • R.M. Samstein et al.

    Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification

    Cell

    (2012)
  • Y.M. Kerdiles et al.

    Foxo transcription factors control regulatory T cell development and function

    Immunity

    (2010)
  • C.L. Bennett et al.

    The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3

    Nat Genet

    (2001)
  • M.W. Teng et al.

    Multiple antitumor mechanisms downstream of prophylactic regulatory T-cell depletion

    Cancer Res

    (2010)
  • P.D. Bos et al.

    Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy

    J Exp Med

    (2013)
  • M.W. Teng et al.

    Conditional regulatory T-cell depletion releases adaptive immunity preventing carcinogenesis and suppressing established tumor growth

    Cancer Res

    (2010)
  • E. Sato et al.

    Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer

    Proc Natl Acad Sci U S A

    (2005)
  • T.J. Curiel et al.

    Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival

    Nat Med

    (2004)
  • G.J. Bates et al.

    Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse

    J Clin Oncol

    (2006)
  • R.P. Petersen et al.

    Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients

    Cancer

    (2006)
  • Q. Gao et al.

    Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection

    J Clin Oncol

    (2007)
  • R.W. Griffiths et al.

    Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival

    Cancer Immunol Immunother

    (2007)
  • Cited by (109)

    • Effector T cell responses unleashed by regulatory T cell ablation exacerbate oral squamous cell carcinoma

      2021, Cell Reports Medicine
      Citation Excerpt :

      These mechanistic insights suggest that therapeutic intervention to manipulate intratumoral Treg cells or augment a T cell-inflamed phenotype may induce unexpected tumor-promoting effects, highlighting the importance of defining the mechanisms driving these effects and delineating biomarkers to identify HNSCC patients at risk of such adverse events. Previous studies have suggested that the influx or expansion of FOXP3+ Treg cells in human solid malignancies may be triggered in response to CD8+ effector T cell infiltration and effector activity.5,29 To examine this relationship in HPV-negative OSCC and other cancers, we used previously defined T cell-type-specific reference gene expression profiles from single-cell RNA sequencing30 to estimate the relative abundance of CD4+ Treg cells, CD4+ conventional T cells, cytotoxic CD8+ T cells, and exhausted CD8+ T cells from bulk gene expression data derived from The Cancer Genome Atlas (TCGA) and Chicago Head and Neck Genomics Cohort (CHGC) datasets31 by mathematical deconvolution using the iPANDA algorithm.32–34

    View all citing articles on Scopus
    View full text