Treg Suppression of Antitumor Adaptive Immunity

Although antigen-presenting cells may be involved in Treg-mediated suppression, in vitro, Treg are able to suppress the proliferation of responder T cells in the absence of other cells (Shevach, 2002). Moreover, the regulation of adaptive responses by Treg can occur not only in secondary lymphoid organs, but also in peripheral tissues, where already-primed effectors reside. Indeed, the correct localization of Treg at inflammatory sites is crucial for their in vivo activity (Siegmund et al., 2005).

CD8+ CTL are considered the main cellular subset responsible for tumor elimination in both humans and mice. Transfer of antigen-specific CTL induces tumor rejection, while the cotransfer of CD4+ Treg abolishes such effects (Chen et al., 2005). In this experimental setting, Treg mainly inhibited the cytotoxicity of CD8+ T lymphocytes rather than their proliferation, survival or cytokines secretion. TGF-p signaling seems critical for Treg immunoregulation, since Treg fail to suppress CD8+ cells genetically engineered to lose responsiveness to this cytokine. TGF-p is an important regulator of CTL functions, altering the transcriptional program of CD8+ lymphocytes toward a defective production of cytotoxic granules (Thomas and Massague, 2005). Similar data have been obtained from a human cytotoxic cell line, which kills autologous tumor cells in vitro unless Treg are present. Cytotoxicity is retained if TGF-p signaling is blocked during the co-culture (Somasundaram et al., 2002). This finding encourages the development of Treg-targeted therapies, since Treg neutralization may fully rescue CTL function and lead to effective tumor eradication. By directly visualizing CTL functions in draining lymph nodes of tumor-bearing mice, Mempel et al. (2006) have described the kinetics of Treg-mediated suppression. Even in the presence of Treg, CTL stored normal amounts of lytic mediators, but they reduced the time of contact with target cells, and the release of granules do not persist long enough to kill the target.

Efficient immune response requires activation of CD4+ T cells. Adoptive immunotherapy combining tumor-specific CD4+ and CD8+ lymphocytes is more efficient than the sole CTL transfer (Antony, 2005). CD4+ T lymphocytes were the first target of Treg suppression identified in vitro (Thornton and Shevach, 1998) and are also consistently inhibited in vivo. Casares et al. (2003) have shown in a murine tumor model that Treg depletion restores IFN-7 production by CD4+ T cells and results in both CD8-dependent and CD8-independent protection from tumor growth. The reactivity of CD4+ T lymphocytes in the presence of tumor is detectable only after proper immunostimulation. Otherwise, these lymphocytes are kept in a strict state of anergy by tumor-derived immunosuppressive signals and fail to produce cytokines upon ex vivo restimulation (Cuenca et al., 2003). A consistent portion of such unresponsive CD4+ lymphocytes is phenotypically and functionally regulatory cells and includes not only naturally arising Treg but also tumor-induced adaptive Treg derived from conversion of non-Treg precursors (Valzasina et al., 2006). Conversion of potential T-helper lymphocytes into Treg is an important issue of T-cell suppression in tumor-bearing hosts. Treg themselves may contribute to the conversion of non-Treg cells by producing suppressive mediators locally. Indeed, it has been demonstrated in vitro that Treg induce a suppressive phenotype in CD4+

target cells (Qiao et al., 2007). Conversion mechanisms will be further discussed in Sect. 4.2.

The complex machinery of anti-tumor response includes the humoral response in addition to cellular immunity. The rejection of Her-2-expressing tumor is mainly mediated by an antibody response against the extracellular portion of the receptor (Reilly et al., 2001). This implies that both B cells and Th2 T cells are involved in anti-tumor immunity. Treg can affect the functions of both lymphocyte subsets. Indeed, Treg can directly kill B lymphocytes (Zhao et al., 2006) and indirectly affect Th2 differentiation, thus hampering the induction of humoral response (Wing and Sakaguchi, 2006).

Treg are likely involved in several steps of anti-tumor response. As recently described by Gallimore and colleagues (Simon et al., 2007), they affect both innate and adaptive responses. On one hand, Treg transfer inhibits the NK-dependent rejection of tumor in the absence of T and B lymphocytes. On the other hand, their depletion, by means of PC61 antibody, synergizes with anti-tumor vaccination by unveiling CD4 and antibody responses.

From this picture, some complexity arises that cannot be easily resolved. Besides the cellular targets of Treg suppression, the phase of immune response in which Treg exert inhibition is still controversial. The observation that some human and murine tumors specifically recruit Treg from the draining lymph nodes implies that Treg are needed for immunosuppression at the site where effector phase takes place. Moreover, depletion of intratumor CD4+ T cells results in efficient eradication only at late stages of murine tumor growth, suggesting that Treg suppress mainly after the priming phase (Yu et al., 2005). Conversely, other clinical and pre-clinical studies show that Treg extensively accumulate also at the draining lymph node where effector T cells encounter antigen-presenting cells and are activated. The actual cognate interaction between Treg and T cells has been described in tumor-draining lymph nodes by intravital imaging studies (Mempel et al., 2006). Moreover, the draining lymph nodes of murine fibrosarcoma contain both Treg and effector cells; suppression occurs by means of partial expression of CD86, which acts as a negative regulator of T cells by CTLA-4 interaction (Hiura et al., 2005). In conclusion, the plasticity of Treg-suppressive function likely licenses them to affect a variety of not mutually exclusive stages of the immune response.

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