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.
Highlights
WHAT ARE Tregs? Regulatory T cells (Tregs) are suppressor cells that are necessary for maintaining immune homeostasis and immunological tolerance to self and which play a key role in limiting excessive and harmful immune responses [1]
PROMOTION OF TUMOR PROGRESSION BY Tregs There is an emerging consensus that effective anti-tumor immunity is characterized by a Thelper1 (Th1)/CD8+ T cell response [4]
Tumor cells and surrounding stromal cells can express these chemokines, which serve to facilitate migration and accumulation of various leukocytes in the tumor [25,26,27]. While some of these leukocytic infiltrates comprise macrophages [28] and myeloid derived suppressor cells (MDSCs) [29] which promote tumor progression and metastasis, a high frequency of infiltrating CD3+ T cells often correlates with improved clinical outcome, e.g., in ovarian and colorectal cancer (CRC) [30, 31]
Summary
WHAT ARE Tregs? Regulatory T cells (Tregs) are suppressor cells that are necessary for maintaining immune homeostasis and immunological tolerance to self and which play a key role in limiting excessive and harmful immune responses [1]. MECHANISMS OF Foxp3+ T CELL ENRICHMENT WITHIN TUMORS Studies have shown that progressing mouse and human tumors can be associated with enhanced Tregs activity and escalating immune suppression [12, 13].
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