The interplay of effector and regulatory T cells in cancer
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
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