Manipulating T regulatory cells in cancer immunotherapy

Malignant tumors express associated antigens that should make them objects of immune attack. Nonetheless, spontaneous immune clearance of established cancer is rare. Recent evidence demonstrates that cancers use active mechanisms to block host antitumor immunity. Significant evidence implicates CD4+CD25+ regulatory T cells (Tregs) as an important mechanism of active immune evasion in cancer. Animal models for cancer demonstrate that Treg depletion improves antitumor immunity and the success of immunotherapy. Thus, blocking Treg function could improve human cancer immunotherapy, where successes have been modest to date. The authors propose four means to block Treg activity: direct elimination; or interference with Treg trafficking, differentiation or function. The fusion toxin denileukin diftitox (Ontak®) eliminates Tregs in some human cancers. The authors discuss their preliminary experience with this agent in human cancer, and discuss progress attempting other strategies to block Treg activity. Reversing tumor-mediated mechanisms hindering host immunity represents a novel approach to tumor immunotherapy.