Regulatory T cells or Tregs are functionally defined as T cells that inhibit an immune response by influencing the activity of another cell type (Shevach, 2004). The most well-defined Treg cells are CD4+CD25+ T cells (Sakaguchi et al, 2001; Shevach, 2002; Von Herrath and Harrison, 2003). The antigen specificity, phenotype, mechanisms of action, and function of Treg cells have been discussed in the literature (Chen et al., 2005; Green et al., 2003; Peng et al., 2004; Wang et al, 2004; Wang and Wang, 2005) and are discussed in Chapter 15 of this book. The immunosuppressive cell surface molecule CTLA-4 is conceptually related to Treg cell function. The role of CTLA-4 and the effects of CTLA-4 blockade in mouse and human cells have been discussed (Chapters 10 and 12). In this chapter, the focus will be the distribution and trafficking of Treg cells in human tumors and the imbalance between Treg cells and conventional T cells in the tumor environment.
A. Imbalance Between Treg Cells and Conventional T Cells in the Bone Marrow
Naturally occurring murine CD4+CD25+ Treg cells differentiate in the thymus
(Francois Bach, 2003; Shevach, 2002; Von Herrath and Harrison, 2003; Wood and Sakaguchi, 2003). In homeostatic conditions in the human and mouse, CD4+CD25 + Treg cells are found primarily in thymus, peripheral blood, lymph nodes, and spleen (Sakaguchi, 2005; Shevach, 2002). Under these conditions, it appears that Treg cells exhibit an equal distribution among the different lymphoid compartments. Notably, more than 25% of CD4+ T cells are phenotypically and functionally Treg cells in normal bone marrow (Zou et al, 2004). The chapter authors' unpublished data further show that the prevalence of Treg cells reach up to 50% in the bone marrow in patients with prostate cancer. The data suggest that in a homeostatic situation, there exists an imbalance between Treg cells and conventional T cells in the bone marrow, and this imbalance is further enforced in cancer patients.
Interestingly, a number of reports have shown that functional memory T cells exist in bone marrow, where they can serve as a site for naive TAA-specific T cell priming (Becker et al., 2005; Feuerer et al, 2003; Mazo et al, 2005; Tripp et al, 1997). TAA-specific T cells isolated from bone marrow in tumor-bearing mice and cancer patients are functional in vitro and are able to prevent tumor growth upon transfer to another host. These observations suggest that these TAA-specific T cells are functionally suppressed in the bone marrow, possibly by Tregs (Feuerer et al., 2001a, 2001b, 2003; Mazo et al., 2005; Tripp et al, 1997). Therefore, it is evident that the bone marrow plays an active role in humoral and cellular lymphocyte immunity.
The notion has been further supported by the observation that large numbers of functional CD4+ Treg cells accumulate in the bone marrow of healthy volunteers and mice (Zou et al., 2004). The observation is confirmed in a mouse model in which a red fluorescent protein reporter was knocked into the endogenous genomic locus for the specific Treg marker FOXP3 (Wan and Flavell, 2005). Further, bone marrow CD4+ Treg cells express functional CXCR4, the receptor for CXCL12, and granulocyte-colony-stimulating factor (G-CSF) mobilizes CD4+ Treg release from bone marrow through reducing marrow CXCL12 (Zou et al., 2004). Interestingly, activation upreg-ulates CXCR4 expression and enables CD4+ Treg cells to migrate to the bone marrow through CXCL12 (Zou et al., 2004). Thus, CXCR4/CXCL12 signals are crucial for activated CD4 + Treg cell bone marrow trafficking. This finding suggests that bone marrow is a preferential site for migration and/or selective retainment of CD4+ Treg cells, and bone marrow may function as an immuno-regulatory organ (Zou et al., 2004).
In summary, Treg cells accumulate to high levels in the bone marrow, and their prevalence appears to be substantially elevated in cancer patients. Bone marrow is a common site for metastasis of many human epithelial tumors, such as those associated with prostate cancer. At present, findings suggest that bone marrow provides an immunosuppressive environment for tumor retention and growth. Imbalance between Treg cells and conventional T cells in the bone marrow may provide an immune shield to facilitate metastatic spread at this site.
B. Imbalance Between Treg Cells and Conventional T Cells in Human Tumors
In the twenty-first century, numerous studies have reported a much higher frequency of CD4+CD25+ T cells in peripheral blood and tumors in patients with a variety of major cancers, including cancers of the breast, colon, rectum, esophagus, stomach, liver, lung, ovary, and pancreas; this finding is also true for individuals with different types of melanomas, leukemias, and lymphomas (Liyanage et al., 2002). This list continues to grow with the rapidly emerging interest of how Tregs can contribute to human tumorigenesis. Together, these data offer compelling evidence of an imbalance between Treg cells and conventional T cells in the tumor environment.
How are elevated levels of Tregs generated in the tumor microenvironment? Evidence suggests several sources, including trafficking of Tregs into the tumor or generation of Tregs at the tumor site by differentiation, DC-induced expansion, or cell conversion. Tregs from the thymus, lymph nodes, bone marrow, and peripheral blood can traffic into the tumor. Regulatory T cells express CCR4, and abundant expression of CCL22 (the ligand for CCR4) in the tumor environment stimulates tumor infiltration by Treg cells (Curiel et al, 2004b). The tumor environment contains molecules capable of suppressing APC differentiation and function, including dysfunctional APCs, which in turn stimulate differentiation of Treg cells. DCs can also stimulate Treg cell expansion in the tumor environment and draining lymph nodes (Sakaguchi, 2001; Shevach, 2002; Zou, 2005). Last, conventional T cells can be converted into regulatory T cells by TGF-p, and high levels of TGF-P are commonly found in the tumor environment. In human ovarian tumor cells, CD4+CD25+ Treg cells block tumor-specific immunity, foster tumor growth, and predict poor patient survival (Curiel et al., 2004b).
In summary, Treg cells abnormally accumulate to high levels in many human tumors, often comprising a major fraction of immune cells present in the tumor environment. Their role is very important since they are likely to be critical in disabling TAA-specific effector T cell immunity in the cancer patient. Manipulation of regulatory T cells, including depletion, blocking trafficking into tumors, or reducing their differentiation and suppressive mechanisms, all represent potential innovative strategies for cancer treatment.
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