CD137 is expressed on diverse immune cell populations, including activated T cells and natural killer (NK) cells. The interaction between CD137 and its ligand CD137L expressed on activated antigen-presenting cells is reported to enhance strong antitumor effects of T cells or NK cells. However, studies on CD137 and CD137L concerning T-cell lymphoma, whose tumor cells can express CD137, have been limited. In this study, we tried to elucidate the role of CD137 and CD137L in cutaneous T-cell lymphoma (CTCL). CTCL cell lines (MyLa, SeAx, Hut78, and HH cells), CD4+CD7- T cells in blood from Sezary syndrome (SS) patients, and a murine lymphoma cell line (EL-4 cells) expressed CD137L as well as CD137 on the cell surface. In addition, CD137 and CD137L expression on CTCL tumor cells in the skin were also confirmed. Furthermore, CD137 and CD137L mRNA expression levels were elevated in CTCL lesional skin. Serum soluble CD137L levels were increased in advanced CTCL patients, compared to healthy controls. We next investigated the involvement of CD137-CD137L interactions in CTCL progression using CTCL cell lines. A neutralizing antibody for CD137L or CD137 inhibited proliferation and cell survival of CTCL cell lines as well as peripheral blood mononuclear cells from SS patients. On the other hand, recombinant CD137-Fc protein promoted tumor proliferation. Moreover, CD137L neutralizing antibody attenuated phosphorylation of ERK1/2, Akt, p38 MAPK, and JNK in CTCL cell lines and CD4+CD7- T cells in blood from SS patients. Blocking CD137L also induced the downregulation of antiapoptotic protein Bcl-2 and phospho-BAD. Thus, our findings prompt a novel therapeutic approach to treat CTCL based on the discovery that CD137-CD137L interactions play a critical role in CTCL development.

Blocking CD137-CD137L interactions inhibits proliferation and survival of cutaneous T-cell lymphoma cells via hampering several signaling pathways