Limited tumor infi ltration by activated T eff ector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma Sergio

The Rockefeller University Press $30.00 J. Exp. Med. Vol. 205 No. 9 2125-2138 www.jem.org/cgi/doi/10.1084/jem.20080099 2125 CD4 + CD25 + Foxp3 + regulatory T cells (T reg cells) are a key checkpoint of T cell activity and are largely responsible for the maintenance of peripheral self-tolerance ( 1 – 4 ). Although their mechanism of action is not yet fully understood, they regulate CD4 and CD8 T cell activity in a cell-extrinsic manner, and their depletion results in greatly enhanced T cell responses to pathogens ( 5 ), self-antigens ( 1 ), and tumors ( 6, 7 ). Increasing evidence for their role in fostering immune privilege in both mouse and human tumors ( 8, 9 ) has fueled interest in attempts to interfere with their number or function for therapeutic benefi t ( 10, 11 ). In preclinical tumor models, CD25-directed T reg cell depletion effi ciently synergizes with a variety of immune-based approaches, but only when depletion occurs prior or close to the time of tumor challenge ( 7, 12, 13 ). Therapeutic T reg cell depletion (i.e., depletion after tumor establishment, which is more relevant to the clinical setting) has either not been thoroughly studied or has generally failed to enhance other immunomodulatory approaches ( 14, 15 ). Although there is no clear explanation for the lack of synergy, a common suggestion is CORRESPONDENCE James P. Allison: [email protected]