Calcineurin inhibitor inhibits tolerance induction by suppressing terminal exhaustion of donor T cells after allo-HCT

• Published in: Blood Vol. 142; no. 5; pp. 477 - 492
• Main Authors: Senjo, Hajime, Harada, Shinpei, Kubota, Shimpei I., Tanaka, Yuki, Tateno, Takahiro, Zhang, Zixuan, Okada, Satomi, Chen, Xuanzhong, Kikuchi, Ryo, Miyashita, Naoki, Onozawa, Masahiro, Goto, Hideki, Endo, Tomoyuki, Hasegawa, Yuta, Ohigashi, Hiroyuki, Ara, Takahide, Hasegawa, Yoshinori, Murakami, Masaaki, Teshima, Takanori, Hashimoto, Daigo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.08.2023
• Subjects: Animals; Calcineurin Inhibitors - pharmacology; Cyclosporine - pharmacology; Graft vs Host Disease - prevention & control; Hematopoietic Stem Cell Transplantation; Immune Tolerance; Leukemia; Mice; Programmed Cell Death 1 Receptor; T-Lymphocytes
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2023019875

•Calcineurin inhibitor treatment after allo-HCT suppresses differentiation of terminal Tex and induces transitory Tex.•Transitory Tex maintains responsiveness of donor T cells to PD-1 blockade and causes cGVHD after adoptive transfer into secondary recipients. [Display omitted] Calcineurin inhibitor–based graft-versus-host disease (GVHD) prophylaxis is standard in allogeneic hematopoietic stem cell transplantation (HCT) but fails to induce long-term tolerance without chronic GVHD (cGVHD) in a considerable number of patients. In this study, we addressed this long-standing question in mouse models of HCT. After HCT, alloreactive donor T cells rapidly differentiated into PD-1+ TIGIT+ terminally exhausted T cells (terminal Tex). GVHD prophylaxis with cyclosporine (CSP) suppressed donor T-cell expression of TOX, a master regulator to promote differentiation of transitory exhausted T cells (transitory Tex), expressing both inhibitory receptors and effector molecules, into terminal Tex, and inhibited tolerance induction. Adoptive transfer of transitory Tex, but not terminal Tex, into secondary recipients developed cGVHD. Transitory Tex maintained alloreactivity and thus PD-1 blockade restored graft-versus-leukemia (GVL) activity of transitory Tex and not terminal Tex. In conclusion, CSP inhibits tolerance induction by suppressing the terminal exhaustion of donor T cells, while maintaining GVL effects to suppress leukemia relapse. Calcineurin inhibitors are a standard part of graft-versus-host disease (GVHD) prophylaxis but do not prevent GVHD in a significant number of patients. Senjo et al studied mouse models of GVHD and demonstrate that calcineurin inhibitors inhibit tolerance by suppressing the development of exhausted T cells. They do, however, promote graft-versus-leukemia (GVL) effects, highlighting the complexity of response to immunosuppression in the prevention of GVHD while preserving GVL activity.