Robust CD8+ T-cell proliferation and diversification after mogamulizumab in patients with adult T-cell leukemia-lymphoma.

Blood advances 2020 May 26

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Skin-related adverse events (AEs) occur frequently in adult T-cell leukemia-lymphoma (ATL) patients treated with mogamulizumab, a humanized anti-CCR4 monoclonal antibody. This study was undertaken to elucidate the mechanisms of mogamulizumab-induced skin-related AEs. We analyzed the T-cell receptor β chain repertoire in ATL patients' peripheral blood mononuclear cells (PBMCs) before and after mogamulizumab. Skin-related AEs were present in 16 patients and were absent in 8 patients. Additionally, we included 11 patients before and after chemotherapy without mogamulizumab. Immune-related gene expression in PBMCs before and after mogamulizumab was also assessed (n = 24). Mogamulizumab treatment resulted in CCR4+ T-cell depletion, and the consequent lymphopenia provoked homeostatic CD8+ T-cell proliferation, as evidenced by increased expressions of CD8B and CD8A, which were significantly greater in patients with skin-related AEs than in those without them. We hypothesize that proliferation is driven by the engagement of self-antigens, including skin-related antigens, in the face of regulatory T-cell depletion. Together with the observed activated antigen presentation function, this resulted in T-cell diversification that was significantly greater in patients with skin-related AEs than in those without. We found that the CD8+ T cells that proliferated and diversified after mogamulizumab treatment were almost entirely newly emerged clones. There was an inverse relationship between the degree of CCR4+ T-cell depletion and increased CD8+ T-cell proliferation and diversification. Thus, lymphocyte-depleting mogamulizumab treatment provokes homeostatic CD8+ T-cell proliferation predominantly of newly emerging clones, some of which could have important roles in the pathogenesis of mogamulizumab-induced skin-related AEs. © 2020 by The American Society of Hematology.

Citation

Masato Saito, Toshihiko Ishii, Itaru Urakawa, Asuka Matsumoto, Ayako Masaki, Asahi Ito, Shigeru Kusumoto, Susumu Suzuki, Takeshi Takahashi, Akimichi Morita, Hiroshi Inagaki, Shinsuke Iida, Takashi Ishida. Robust CD8+ T-cell proliferation and diversification after mogamulizumab in patients with adult T-cell leukemia-lymphoma. Blood advances. 2020 May 26;4(10):2180-2191