CCR8 is a new therapeutic target in cutaneous T-cell lymphomas

T-cell lymphomas are a heterogeneous group of malignancies involving T lymphocytes, with a poor prognosis. Mycosis fungoides (MF) and S?ezary syndrome (SS) are the most frequent cutaneous T-cell lymphomas (CTCL). The circulating clonal tumor T cells (S?ezary cells) express CD4 and may lose expression of CD7 and CD26, while exhibiting in most cases aberrant expression of CD158k (KIR3DL2).1,2 Long-term responses are rare in advanced-stage CTCL, and new treatments are needed. Recently, treatment with anti-CCR4 monoclonal antibody (mogamulizumab) has improved progression-free survival (PFS) in CTCL.3 CCR4 is expressed by S?ezary cells and peripheral blood activated regulatory T cells (Treg)4; depletion of CCR4+ skin-infiltrating and circulating Treg by mogamulizumab5 is associated with autoimmune adverse events.6,7 Moreover, resistance to mogamulizumab may occur through loss of CCR4 expression by tumor T cells.8,9 Besides CCR4, S?ezary cells express several Treg markers and immune checkpoints, such as PD1,10 CD39,11 and T cell Immunoreceptor with Ig and ITIM domains.12 This led us to investigate the expression of CCR8 (CD198), a chemokine receptor involved in the homing of lymphocytes to skin.13 CCR8 is expressed by skin resident memory T cells,14 which are suspected to be the tumor cells of origin in MF.15 CCR8 is also strongly expressed by tumor-infiltrating Treg involved in immune escape while expression on peripheral blood Treg is lower.16,17 Depletion of CCR8+ Treg exerted a strong antitumor effect independently or in combination with PD-1 inhibitor in tumor mouse models.18 Anti-CCR8 monoclonal antibody depleted fewer peripheral Tregs than anti-CCR4 monoclonal antibody,18 suggesting that treatment with therapeutic anti-CCR8 antibody may avoid immune side effects associated with mogamulizumab while sparing antitumor immunity.18 Therapeutic depletion of CCR8-expressing cells could thus eliminate tumor cells and activate the antitumor immunity in T-cell lymphomas while avoiding immune side effects.