The regulatory T cells (Tregs) with the most potent immunosuppressive activity are the effector regulatory T cells (eTregs) with a CD45RA-Foxp3++CCR4+ phenotype. Adult T cell leukemia (ATL) cells often share the Treg phenotype and also express CCR4. Although mogamulizumab, a monoclonal antibody to CCR4, shows marked antitumor effects against ATL and peripheral T-cell lymphoma, concerns have been raised that it may induce severe autoimmune immunopathology by depleting eTregs. Here we present two ATL cases that responded to mogamulizumab, but developed a severe skin rash and autoimmune brainstem encephalitis. Deep sequencing of the TCR revealed that ATL cells and naturally occurring Tregs within the cell population with a Treg phenotype can be clearly distinguished according to CADM1 expression. The onset of skin rash and brainstem encephalitis was coincident with eTreg depletion from the peripheral blood, whereas ATL relapses were coincident with eTreg recovery. These results imply that eTreg numbers in the peripheral blood sensitively reflect the equilibrium between antitumor immunity and autoimmunity, and that mogamulizumab might suppress ATL until the eTreg population recovers. Close monitoring of eTreg numbers is crucial if we are to provide immunomodulatory treatments that target malignancy without severe adverse events.
- Received December 10, 2015.
- Revision received March 24, 2016.
- Accepted April 19, 2016.
- Copyright ©2016, American Association for Cancer Research.