2.3.2. Therapy against Tregs

Tregs within tumor site are crucial components for tumor immunosuppression. Therefore depletion or functional inhibition could be a promising strategy for inducing antitumor immunity. Selective depletion of Tregs can be achieved by anti-CD25 antibody, which significantly improves T cell-mediated tumor regression [58, 62]. CTLA4 is another potential target. Administration of CTLA4-specific antibody with cancer vaccine effectively reduces Tregs and improves immunity [58, 62]. However, blocking of CTLA4 is strongly associated with the induction of autoimmune manifestation [58, 62]. Furthermore, this antibody fails to induce depletion of peripheral Tregls. An alternative therapeutic approach for the depletion of Tregs is the use of denileukin diftitox (Ontak®), which is a ligand toxin fusion consisting of full-length IL-2 fused to the enzymatically active and translocating domains of diphtheria toxin. The complex inhibits protein synthesis, leading to apoptosis of Tregs [3]. A recent study indicates that treatment with this complex significantly reduces the absolute number of peripheral Tregs and increases effector T-cell activation in different cancer patients. However, this requires further detailed investigation.

#### 2.3.3. CuNG-mediated Treg modulation

Another promising approach for blocking the infiltration or functional modulation of Treg includes the application of novel metal containing drug, e.g., CuNG that might have therapeutic advantages. Previously, it was found that a sizable proportion of CD4+ cells of drugresistant tumor-bearing mice exhibited T-regulatory markers (CD25 and Foxp3). After in vivo treatment of CuNG, only a few CD25+Foxp3+ cells were observed in tumor-bearing mice [22, 25]. Moreover, CuNG-treated TAMs could modulate TGF-β producing CD4+CD25+ T cells toward IFN-γ producing T cells with concomitant decrease in the level of FoxP3 expression, indicating that Treg can be reprogrammed toward Th1 phenotype. However, this approach requires further investigations.
