Tumor-infiltrating regulatory T cells: Phenotype, role, mechanism of expansion in situ and clinical significance

In immunocompetent individuals, the immune system initially eradicates potentially tumorigenic cells as they develop, a capacity that is progressively lost when malignant cells acquire alterations that sustain immunosubversion and/or immunoevasion. One of the major mechanisms whereby cancer cells block antitumor immune responses involves a specific class of immunosuppressive T cells that-in the vast majority of cases-express the Forkhead box P3 (FOXP3) transcription factor. Such FOXP3⁺ regulatory T cells (Tregs) accumulate within neoplastic lesions as a result of several distinct mechanisms, including increased infiltration, local expansion, survival advantage and in situ development from conventional CD4⁺ cells. The prognostic/predictive significance of tumor infiltration by Tregs remains a matter of debate. Indeed, high levels of intratumoral Tregs have been associated with poor disease outcome in cohorts of patients affected by multiple, but not all, tumor types. This apparent discrepancy may relate to the existence of functionally distinct Treg subsets, to the fact that Tregs near-to-invariably infiltrate neoplastic lesions together with other cells from the immune system, notably CD4⁺ and CD8⁺ T lymphocytes and/or to peculiar features of some oncogenic programs that involve a prominent pro-inflammatory component. In this review, we will discuss the phenotype, function and clinical significance of various Treg subsets.