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Review
. 2018 Jan 15;200(2):415-421.
doi: 10.4049/jimmunol.1701188.

Unlocking the Complexities of Tumor-Associated Regulatory T Cells

Jaime L Chao  1 , Peter A Savage  2
Affiliations
Review

Unlocking the Complexities of Tumor-Associated Regulatory T Cells

Jaime L Chao et al. J Immunol. .

Abstract

Regulatory T (Treg) cells are found at elevated densities in many human cancers and are thought to be a major barrier to the generation of robust antitumor T cell responses. In this review, we discuss recent advances in the understanding of tumor-associated Treg cell diversity and function. Emerging evidence indicates that the transcriptional program of Treg cells infiltrating human cancers may represent a composite program blending a tissue-associated expression signature with an additional tumor-specific signature common to Treg cells from multiple cancer types. Studies in mouse models have defined unique molecular pathways required for Treg cell function in the tumor context that can be manipulated to selectively dampen intratumoral Treg cell activity. Finally, an expanding body of work has revealed diverse functions for Treg cells in nonlymphoid tissues that are unrelated to immune suppression, suggesting a need to explore functions of intratumoral Treg cells beyond the regulation of antitumor immunity.

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Figures

Figure 1
Figure 1. Hallmarks of tumor-infiltrating Treg cells
Conceptual model highlighting the phenotypic and functional diversity of Treg cells in lymphoid organs, non-lymphoid tissue sites, and tumor lesions. Central Treg cells (cTregs) and effector Treg cells (eTregs) in the lymph nodes and spleen are thought to mediate the suppression of autoimmune reactions and the maintenance of immune homeostasis. cTreg cells are characterized by a quiescent “naive” phenotype, and can differentiate into activated-phenotype eTreg cells in an antigen-dependent process. Tissue-associated Treg cells present in different non-lymphoid sites exhibit tissue-specific transcriptional programs unique to the tissue of residence, and can mediate diverse context-dependent functions that are independent of immune suppression. The mechanisms driving Treg cell enrichment and expansion within tumors are unknown, but may involve responsiveness to antigen, chemokines, and inflammatory mediators. Intratumoral Treg cells are characterized by the following hallmarks: 1) evidence of oligoclonal expansion; 2) a composite transcriptional signature that blends a tissue-specific Treg cell signature associated with the tissue of cancer origin with a conserved tumor-specific signature that is common to Treg cells from different cancer types; 3) high expression of common Treg markers known to function as immunomodulatory receptors, including CTLA-4, PD-1, TIGIT, OX40, and GITR; 4) expression of transcripts encoding proteins with undefined roles in intratumoral Treg cell biology, including CCR8, MAGEH1, IL1R2, TFRC, and FCRL3. Beyond suppression of anti-tumor T cell responses, additional functions of intratumoral Treg cells have yet to be clearly defined. The arrow suggests a precursor-product relationship, which has been defined for the cTreg-to-eTreg transition, but remains hypothetical for tissue-associated and intratumoral Treg cell populations.
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