Depletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab

• Published in: Nature communications Vol. 12; no. 1; pp. 7280 - 13
• Main Authors: Maeda, Yuka, Wada, Hisashi, Sugiyama, Daisuke, Saito, Takuro, Irie, Takuma, Itahashi, Kota, Minoura, Kodai, Suzuki, Susumu, Kojima, Takashi, Kakimi, Kazuhiro, Nakajima, Jun, Funakoshi, Takeru, Iida, Shinsuke, Oka, Mikio, Shimamura, Teppei, Doi, Toshihiko, Doki, Yuichiro, Nakayama, Eiichi, Ueda, Ryuzo, Nishikawa, Hiroyoshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.12.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 631/250/251/1574; 631/67/580/1884/2323; 692/4017; 692/4028/67/1059/2325; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized - therapeutic use; Anticancer properties; Antineoplastic Agents - therapeutic use; Antitumor activity; Cancer; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - metabolism; Cell differentiation; Chemokine receptors; Depletion; Dose-Response Relationship, Drug; Effector cells; Female; Homeostasis; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunological memory; Immunoregulation; Immunotherapy; Killer Cells, Natural - drug effects; Killer Cells, Natural - metabolism; Lymphocytes; Lymphocytes T; Male; Memory cells; Memory T Cells - drug effects; Middle Aged; Monoclonal antibodies; multidisciplinary; Neoplasms - drug therapy; Neoplasms - immunology; Patients; Phenotypes; Receptors, CCR4 - antagonists & inhibitors; Receptors, CCR4 - metabolism; Science; Science (multidisciplinary); Solid tumors; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - metabolism; Targeted cancer therapy; Treatment Outcome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27574-0

Regulatory T (Treg) cells are important negative regulators of immune homeostasis, but in cancers they tone down the anti-tumor immune response. They are distinguished by high expression levels of the chemokine receptor CCR4, hence their targeting by the anti-CCR4 monoclonal antibody mogamulizumab holds therapeutic promise. Here we show that despite a significant reduction in peripheral effector Treg cells, clinical responses are minimal in a cohort of patients with advanced CCR4-negative solid cancer in a phase Ib study (NCT01929486). Comprehensive immune-monitoring reveals that the abundance of CCR4-expressing central memory CD8 + T cells that are known to play roles in the antitumor immune response is reduced. In long survivors, characterised by lower CCR4 expression in their central memory CD8 + T cells possessed and/or NK cells with an exhausted phenotype, cell numbers are eventually maintained. Our study thus shows that mogamulizumab doses that are currently administered to patients in clinical studies may not differentiate between targeting effector Treg cells and central memory CD8 + T cells, and dosage refinement might be necessary to avoid depletion of effector components during immune therapy. Elimination of regulatory T cells via the anti-CCR4 monoclonal antibody, mogamulizumab, is expected to augment anti-tumour immune response. Authors show here that although regulatory T cell targeting is successful, clinical improvement remains minimal in patients with solid tumours due to concomitant and unintended depletion of central memory CD8 + T cells.