Home Sweet Home: The Tumor Microenvironment as a Haven for Regulatory T Cells

Abstract

CD4+Foxp3+ regulatory T cells (Tregs) have a fundamental role in maintaining immune balance by preventing autoreactivity and immune-mediated pathology. However this role of Tregs extends to suppression of anti-tumor immune responses and remains a major obstacle in the development of anti-cancer vaccines and immunotherapies. This feature of Treg activity is exacerbated by the discovery that Treg frequencies are not only elevated in the blood of cancer patients, but are also significantly enriched within tumors in comparison to other sites. These observations have sparked off the quest to understand the processes through which Tregs become elevated in cancer-bearing hosts and to identify the specific mechanisms leading to their accumulation within the tumor microenvironment. This manuscript reviews the evidence for specific mechanisms of intra-tumoral Treg enrichment and will discuss how this information may be utilized for the purpose of manipulating the balance of tumor-infiltrating T cells in favor of anti-tumor effector cells.

Human lung tumor FOXP+ Tregs upregulate four “Treg-locking” transcription factors

“…Increased LN Treg numbers were associated with decreased CD8 + T cells within LC LNs, consistent with a recent observation that, in lung adenocarcinoma, Tregs restrict antitumor CD8 + responses (2). We explored various mechanisms to explain enrichment of Tregs in tumors, including expansion in situ, local iTreg conversion, and enhanced Treg recruitment (14). Our data did not support an enhanced division rate of intratumoral Tregs.…”

“…We also observed a cancer-specific decrease in the percentage of CD8 + , but not CD4 + , cells in pulmonary LNs ( Figure 2D and Supplemental Figure 3C), which may reflect ongoing suppression of antitumor cytotoxic T cell immune responses. Several mechanisms have been suggested to explain the Treg enrichment observed in various tumors (14), including their expansion in situ, local inducible Treg (iTreg) conversion, and enhanced trafficking to tumors, and these were explored in our study.…”

IL-1R1 is expressed on both Helios+ and Helios−FoxP3+CD4+ T cells in the rheumatic joint

“…Such effects have also been demonstrated in other disease settings, such as type 1 diabetes and cancer [27][28][29] …”

TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies

“…This environment is in large part imprinted by Tregs (14)(15)(16). At the time of tumor emergence in mice, competition arises between antitumor Tregs and Teffs (17).…”