Human regulatory T cells (Treg) and their response to cancer

ABSTRACT

Introduction: Regulatory T cells (Treg) and their role in health and disease is being intensively investigated. Today, human Treg emerge as a highly heterogeneous subset of CD4 + T cells which mediate immune suppression but also regulate responses of non-immune cells. In cancer, Treg occupy a critical although not yet entirely understood role.

Areas covered: Newly acquired insights into Treg indicate a much greater plasticity and functional heterogeneity of this T cell subset than was previously known. Functional redundancy of Treg and their interactions with a variety of immune and non-immune cellular targets emphasize the central role Treg play in cancer. Treg not only regulate the host responses to cancer; they may also regulate responses to immune therapies. The impact of immune checkpoint blockade on Treg survival, stability, and suppressive activity remains to be elucidated. T cell reprogramming by tumor-derived factors, including tumor-derived exosomes (TEX), plays a key role in shaping the Treg repertoire in the tumor microenvironment (TME). The reprogrammed or induced iTreg acquire capabilities to strongly down-regulate anti-tumor immune responses by mechanisms that are specific for each TME. Therapeutic silencing of such Treg calls for the discrimination of ‘bad’ from ‘good’ Treg subsets, an approach that remains elusive in the absence of a definitive ‘Treg signature.’

Expert opinion: Context-related plasticity and heterogeneity of Treg in the TME are significant barriers to selective therapeutic depletion of those Treg subsets that are reprogramed by the tumor to suppress anti-tumor immunity.

KEYWORDS:

• Regulatory T cells
• Treg
• cancer
• tumor microenvironment
• immune suppression

Article highlights

• Elevated Treg/Teff cell ratios in tumors may be prognostically useful

• iTreg accumulating in the tumor microenvironment (TME) are reprogrammed

• Origins of tTreg, pTreg, and iTreg

• Treg nomenclature and control of cancer prognosis by eTreg

• Mechanisms involved in Treg-mediated suppression

• Up-regulated ICIRs on Treg and Treg signaling in the TME

• Emerging role of tumor-derived exosomes in Treg reprogramming

• Attempts at silencing ‘bad’ Treg in cancer

• Treg modulation by immune checkpoint inhibition

• Contextual heterogeneity and broad functional profile of Treg

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work has been supported in part by NIH grants R01 CA168628 and R21 CA204644 to TLW. This project used UPMC Hillman Cancer Center shared resources that are supported in part by NIH award P30 CA047904.