Daniel S. Leventhal

Aire-Dependent Thymic Development of Tumor-Associated Regulatory T Cells

On the Origin of Tumor Tregs The tumor microenvironment is often seeded with regulatory T cells (Tregs), which inhibit antitumor immunity. Using mice with genetically driven prostate cancer, Malchow et al. (p. 1219; see the Perspective by Joshi and Jacks) found a population of Tregs that were enriched in the prostate of tumor-bearing mice. Surprisingly, these cells were also present in female mice and were found to be specific, not for a tumor-specific antigen, but rather for an antigen normally expressed in the prostate. Prostate antigen–specific Tregs arose in the thymus and their selection was dependent on Aire, a protein that drives the expression of tissue-specific antigens in the thymus. Thus, Tregs that seed tumors likely arise in the thymus, are not necessarily tumor-specific, and are recruited and/or expand in an organ when a tumor arises. Prostate tumors in mice recruit thymus-derived regulatory T cells that are specific for tissue autoantigens. [Also see Perspective by Joshi and Jacks] Despite considerable interest in the modulation of tumor-associated Foxp3+ regulatory T cells (Tregs) for therapeutic benefit, little is known about the developmental origins of these cells and the nature of the antigens that they recognize. We identified an endogenous population of antigen-specific Tregs (termed MJ23 Tregs) found recurrently enriched in the tumors of mice with oncogene-driven prostate cancer. MJ23 Tregs were not reactive to a tumor-specific antigen but instead recognized a prostate-associated antigen that was present in tumor-free mice. MJ23 Tregs underwent autoimmune regulator (Aire)–dependent thymic development in both male and female mice. Thus, Aire-mediated expression of peripheral tissue antigens drives the thymic development of a subset of organ-specific Tregs, which are likely coopted by tumors developing within the associated organ.

Basic principles of tumor-associated regulatory T cell biology

Due to the critical role of forkhead box (Fox)p3(+) regulatory T cells (Tregs) in the regulation of immunity and the enrichment of Tregs within many human tumors, several emerging therapeutic strategies for cancer involve the depletion or modulation of Tregs, with the aim of eliciting enhanced antitumor immune responses. Here, we review recent advances in understanding of the fundamental biology of Tregs, and discuss the implications of these findings for current models of tumor-associated Treg biology. In particular, we discuss the context-dependent functional diversity of Tregs, the developmental origins of these cells, and the nature of the antigens that they recognize within the tumor environment. In addition, we highlight critical areas of focus for future research.

Dendritic Cells Coordinate the Development and Homeostasis of Organ-Specific Regulatory T Cells

Although antigen recognition mediated by the T cell receptor (TCR) influences many facets of Foxp3(+) regulatory T (Treg) cell biology, including development and function, the cell types that present antigen to Treg cells in vivo remain largely undefined. By tracking a clonal population of Aire-dependent, prostate-specific Treg cells in mice, we demonstrated an essential role for dendritic cells (DCs) in regulating organ-specific Treg cell biology. We have shown that the thymic development of prostate-specific Treg cells required antigen presentation by DCs. Moreover, Batf3-dependent CD8α(+) DCs were dispensable for the development of this clonotype and had negligible impact on the polyclonal Treg cell repertoire. In the periphery, CCR7-dependent migratory DCs coordinated the activation of organ-specific Treg cells in the prostate-draining lymph nodes. Our results demonstrate that the development and peripheral regulation of organ-specific Treg cells are dependent on antigen presentation by DCs, implicating DCs as key mediators of organ-specific immune tolerance.

Shaping the repertoire of tumor-infiltrating effector and regulatory T cells.

Many tumors express antigens that can be specifically or selectively recognized by T lymphocytes, suggesting that T‐cell‐mediated immunity may be harnessed for the immunotherapy of cancer. However, since tumors originate from normal cells and evolve within the context of self‐tissues, the immune mechanisms that prevent the autoimmune attack of normal tissues function in parallel to restrict anti‐tumor immunity. In particular, the purging of autoreactive T cells and the development of immune‐suppressive regulatory T cells (Tregs) are thought to be major barriers impeding anti‐tumor immune responses. Here, we discuss current understanding regarding the antigens recognized by tumor‐infiltrating T‐cell populations, the mechanisms that shape the repertoire of these cells, and the role of the transcription factor autoimmune regulator (Aire) in these processes. Further elucidation of these principles is likely to be critical for optimizing emerging cancer immunotherapies, and for the rational design of novel therapies exhibiting robust anti‐tumor activity with limited toxicity.

Organ-specific regulatory T cells of thymic origin are expanded in murine prostate tumors

Little is known about the relative contributions of self-specific regulatory T cells (Tregs) of thymic origin and induced Tregs generated extrathymically to the pool of tumor-infiltrating Tregs. We have recently demonstrated that thymic-derived Tregs reactive to a prostate-associated self antigen are highly and recurrently enriched within oncogene-driven murine prostate cancers.