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

Abstract

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 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 chronic GVHD. Transitory-Tex maintained alloreactivity and thus PD-1 blockade restored graft-versus-leukemia (GVL) activity of transitory-Tex, 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.

Research Highlights

“…Although widespread adoption of prophylaxis with calcineurin inhibitors (CNIs) has improved the rates of acute graft-versus-host-disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HCT), the incidence of chronic GVHD (cGVHD) is rising. 1,2 cGVHD has significant impacts on long-term quality of life and is a primary cause of late morbidity and mortality after allo-HCT. The pathophysiology is complex, involving dysregulation of immune effector populations and disruption of central and peripheral tolerance pathways.…”

“…Senjo et al 1 leverage a mouse model of HCT to explore how CNIs may affect tolerance and development of cGVHD. The authors demonstrated that donor T cells rapidly differentiate into terminally exhausted T cells (Tex) after HCT in the absence of CNI, in part because of upregulation of TOX (thymocyte selection-associated HMG BOX), a master regulator of T-cell exhaustion.…”

“…Through a series of refined mouse models, Senjo et al 1 provide novel insights into the role of CNI on the exhaustion pathway of donor T cells after allo-HCT, identifying a novel CNI-induced transitory Tex population, which could serve as a future therapeutic target. These results highlight the possible relevance of the timing of CNI initiation posttransplant, serving as a reminder of the importance of understanding the influence of immunosuppressive agents on posttransplant immunity.…”

Separation of GVL from GVHD -location, location, location

“…Calcineurin inhibitors inhibit T-cell exhaustion by inhibiting expression of a master regulator of T cell exhaustion, TOX ( 34 ). In experimental HCT, GVHD prophylaxis with calcineurin inhibitors suppresses differentiation of transitory-Tex to terminal-Tex, resulting in persistent alloreactivity and induction of chronic GVHD ( 35 ). T cell dysfunction of terminal-Tex is irreversible and non-responsive to immune checkpoint inhibitors (ICI), while ICI enhance proliferation and effector functions of Tpex and transitory-Tex ( 36 ).…”

“…T cell dysfunction of terminal-Tex is irreversible and non-responsive to immune checkpoint inhibitors (ICI), while ICI enhance proliferation and effector functions of Tpex and transitory-Tex ( 36 ). Therefore, calcineurin-induced transitory-Tex could be a promising therapeutic target to restore GVL effects by ICI but with a risk of GVHD exacerbation ( 35 ).…”