PMID- 32433748 OWN - NLM STAT- MEDLINE DCOM- 20210514 LR - 20210925 IS - 2473-9537 (Electronic) IS - 2473-9529 (Print) IS - 2473-9529 (Linking) VI - 4 IP - 10 DP - 2020 May 26 TI - Robust CD8+ T-cell proliferation and diversification after mogamulizumab in patients with adult T-cell leukemia-lymphoma. PG - 2180-2191 LID - 10.1182/bloodadvances.2020001641 [doi] AB - 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 beta 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. CI - (c) 2020 by The American Society of Hematology. FAU - Saito, Masato AU - Saito M AD - R&D Division, Kyowa Kirin Co. Ltd., Shizuoka, Japan. FAU - Ishii, Toshihiko AU - Ishii T AD - R&D Division, Kyowa Kirin Co. Ltd., Shizuoka, Japan. FAU - Urakawa, Itaru AU - Urakawa I AD - R&D Division, Kyowa Kirin Co. Ltd., Shizuoka, Japan. FAU - Matsumoto, Asuka AU - Matsumoto A AD - R&D Division, Kyowa Kirin Co. Ltd., Shizuoka, Japan. FAU - Masaki, Ayako AU - Masaki A AD - Department of Hematology and Oncology and. AD - Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan. FAU - Ito, Asahi AU - Ito A AD - Department of Hematology and Oncology and. FAU - Kusumoto, Shigeru AU - Kusumoto S AD - Department of Hematology and Oncology and. FAU - Suzuki, Susumu AU - Suzuki S AD - Department of Hematology and Oncology and. AD - Department of Tumor Immunology, Aichi Medical University School of Medicine, Aichi, Japan. FAU - Takahashi, Takeshi AU - Takahashi T AD - R&D Division, Kyowa Kirin Co. Ltd., Shizuoka, Japan. AD - Medical Affairs Department, Kyowa Kirin Co. Ltd., Tokyo, Japan. FAU - Morita, Akimichi AU - Morita A AD - Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan; and. FAU - Inagaki, Hiroshi AU - Inagaki H AD - Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan. FAU - Iida, Shinsuke AU - Iida S AD - Department of Hematology and Oncology and. FAU - Ishida, Takashi AU - Ishida T AD - Department of Hematology and Oncology and. AD - Department of Immunology, Nagoya University Graduate School of Medicine, Aichi, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood Adv JT - Blood advances JID - 101698425 RN - 0 (Antibodies, Monoclonal, Humanized) RN - YI437801BE (mogamulizumab) SB - IM MH - Adult MH - Antibodies, Monoclonal, Humanized MH - CD8-Positive T-Lymphocytes MH - Cell Proliferation MH - Humans MH - *Leukemia-Lymphoma, Adult T-Cell/drug therapy MH - Leukocytes, Mononuclear PMC - PMC7252545 COIS- Conflict-of-interest disclosure: M.S. is an employee of and stockholder in Kyowa Kirin Co., Ltd. T. Ishii, I.U., and Asuka Matsumoto are employees of Kyowa Kirin Co., Ltd. S.K. has received research funding and honoraria from Chugai Pharmaceutical Co., Ltd. and has received research funding from Kyowa Kirin Co., Ltd. T.T. is an employee of Kyowa Kirin Co., Ltd. S.I. has received research funding from Kyowa Kirin, Chugai Pharmaceutical Co., Ltd., Takeda, Ono Pharmaceutical, Janssen Pharmaceuticals, Sanofi, Bristol-Myers Squibb, MSD, Celgene, Daiichi Sankyo, Gilead Sciences, and AbbVie and has received honoraria from Janssen Pharmaceuticals, Celgene, Takeda, Daiichi Sankyo, Ono Pharmaceutical, and Bristol-Myers Squibb. T. Ishida has received research funding from Kyowa Kirin Co., Ltd., Bayer AG, and Celgene K.K. and has honoraria from Kyowa Kirin Co., Ltd., Celgene K.K., and Mundipharma K.K. The remaining authors declare no competing financial interests. EDAT- 2020/05/21 06:00 MHDA- 2021/05/15 06:00 PMCR- 2020/05/20 CRDT- 2020/05/21 06:00 PHST- 2020/02/10 00:00 [received] PHST- 2020/04/13 00:00 [accepted] PHST- 2020/05/21 06:00 [entrez] PHST- 2020/05/21 06:00 [pubmed] PHST- 2021/05/15 06:00 [medline] PHST- 2020/05/20 00:00 [pmc-release] AID - S2473-9529(20)31294-5 [pii] AID - 2020/ADV2020001641 [pii] AID - 10.1182/bloodadvances.2020001641 [doi] PST - ppublish SO - Blood Adv. 2020 May 26;4(10):2180-2191. doi: 10.1182/bloodadvances.2020001641.