Treg in Murine Tumors

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Berendt and North (1980) first described T lymphocytes with suppressive activity in mice bearing an immunogenic fibrosarcoma, which prevented adoptively transferred effector cells from inducing tumor regression. The almost 20 years of silence that followed this pioneer observation were mainly due to the absence of a marker that specifically identified such suppressor T cells. Subsequently, a CD4+ T-cell population similar to North's suppressor T cells was found involved in autoimmune manifestations. These cells were characterized by the expression of the surface marker CD25 and shown to be responsible for the control of autoimmunity. Indeed, removal of CD25-positive T cells led to autoimmune disease in several organs and reconstitution of the eliminated population reverted the pathological status (Powrie and Mason, 1990; Sakaguchi et al., 1985; Sugihara et al., 1988). This population was found to be anergic and suppressive in vitro and proposed to be responsible for autoimmunity induced by thymectomy 3 days postnatal, in accordance to the key role of thymus in central tolerance (Itoh et al., 1999).

The knowledge acquired in the field of autoimmunity was soon translated into that of tumor immunology by Sakaguchi and collaborators in 1999 (Shimizu et al., 1999). Administration of anti-CD25-depleting antibody (PC61 clone) prior to injection of a leukemia cell line induced CTL- and NK-mediated tumor rejection. Similar results were also obtained in other laboratories toward hematological and solid tumor models (Golgher et al., 2002; Jones et al., 2002; Onizuka et al., 1999). Concurrent depletion of effector T cells, activated by concomitant immunity or vaccination, represents the main limit of using the same treatment in a therapeutic rather than preventive setting (Onizuka et al., 1999). Other limitations of the depletion approach will be extensively discussed in Sect. 6.1.

Sakaguchi proposed the term of regulatory T cells as "a common basis between tumor immunity and autoimmunity" (Shimizu et al., 1999). Anti-tumor and antiself responses are strictly linked. Indeed, mice rejecting the melanoma cell line B16F10 because of Treg depletion also mounted efficient immunity toward the self melanocyte differentiation antigen tyrosinase (Jones et al., 2002). The immune response elicited by Treg depletion was directed against tumor antigens shared among different histotypes, since mice rejecting the colon carcinoma cell line CT26 were protected against tumors of different origin (Golgher et al., 2002). This observation stressed the possibility that Treg removal might allow auto-reactive T cells to target self-antigens expressed by tumor cells, being potentially dangerous for normal tissues.

Synergistic effects of CTLA-4 blockade and Treg depletion in inducing anti-tumor and anti-self responses following melanoma vaccination indicate that CTLA-4 is not the suppressive element on Treg (Sutmuller et al., 2001). The combined treatments were likely acting on different levels of autoimmunity control. The dominant Treg-mediated tolerance was broken by CD25 depletion, while blocking the inhibitory receptor CTLA-4 reversed the recessive tolerance of auto-reactive lymphocytes. The protection from melanoma growth was strictly accompanied by depigmentation caused by immune attack of self-antigens expressed by melanocytes. However, the sole Treg depletion is sufficient to induce vitiligo in the course of melanoma immunotherapy. In a setting in which lymphocytes, transgenic for the TCR to the melanoma antigen gp100, were adoptively transferred in B16-bearing mice, naturally occurring Treg were suppressing both T-helper and antigen-specific CD8+ cells. Their removal was also associated with tumor rejection and vitiligo (Antony et al., 2005).

Depletion of CD4+ lymphocytes, either alone or in combination with GM-CSF, leads to complete rejection of B16 melanoma cell line (Turk et al., 2004). Here for the first time an alternative approach was proposed: to target Treg by functionally inhibiting them rather than depleting them. Indeed, Sakaguchi had previously demonstrated that the stimulation of GITR on Treg reversed their suppres-sive function (Shimizu et al., 2002). When applied to cancer immunotherapy, this approach promoted concomitant immunity. GITR triggering consistently improves vaccine-induced immunity and reverts tolerance to tumor antigens without producing overt autoimmune side effects when administered within the tumor (Cohen et al., 2006; Ko et al., 2005; Ramirez-Montagut, 2006). In all of these models, however, GITR stimulation appeared mainly to boost effector T cells rather than inhibit Treg.

Since Treg heavily infiltrate tumors of different origin, targeting Treg locally rather than systemically could avoid generalized autoimmune manifestations. This issue has been investigated by Yu et al. (2005) who demonstrated that Treg ablation within the tumor mass leads to the complete rejection of advanced highly immuno-genic lesions. This result was achieved by administration of anti-CD4 that, instead of anti-CD25-depleting antibody, allowed eliminating CD4+ Treg while sparing CD8+CD25+-activated effector cells. This model highlighted that Treg are capable of actively hindering the endogenous immune response that might be generated against tumors.

In transgenic mice carrying the Her-2/neu under the MMTV promoter, the oncogene is a self-antigen. Although progressing tumor induces Treg expansion (Ambrosino, 2006 and our unpublished observation), natural Treg seem to have no role during earlier immunosurveillance (Chiodoni et al., 2006).

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