PTCy ameliorates GVHD by restoring regulatory and effector T-cell homeostasis in recipients with PD-1 blockade

Shuntaro Ikegawa, Yusuke Meguri, Takumi Kondo, Hiroyuki Sugiura, Yasuhisa Sando, Makoto Nakamura, Miki Iwamoto, Yoshinobu Maeda, Ken Ichi Matsuoka

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a significant cause of morbidity and mortality. Regulatory T cells (Tregs) are critical mediators of immune tolerance after allo-HSCT. Clinical studies have indicated that programmed cell death 1 (PD-1) blockade before allo-HSCT involves a risk of severe GVHD. However, the mechanisms underlying GVHD induction resulting from PD-1 blockade remain unclear. We investigated the impact of PD-1 expression of donor T cells on T-cell reconstitution and GVHD using murine models. We first demonstrated that inhibition of PD-1 signaling induced aggressive expansion of CD41 conventional T cells; however, Tregs could not maintain expansion because of high susceptibility to apoptosis, resulting in discordant immune recovery and subsequent development of severe GVHD. We then evaluated the impact of posttransplantation cyclophosphamide (PTCy) on abnormal T-cell reconstitution after PD-1 blockade. PTCy efficiently ameliorated GVHD after transplantation from a PD-12/2 donor and extended overall survival by safely regulating the proliferation and apoptosis of T-cell subsets. Notably, in the first 2 weeks after administration of PTCy, Tregs regained their ability to continuously proliferate, resulting in well-balanced reconstitution of donor T-cell subsets. In conclusion, the influence of PD-1 blockade differed within T-cell subsets and caused unbalanced reconstitution of T-cell subsets, resulting in severe GVHD. PTCy successfully restored T-cell homeostasis and ameliorated GVHD induced by PD-12/2 donor T cells. These findings may help explain the pathophysiology behind the observation that PTCy may mitigate the incidence and impact of GVHD associated with prior exposure to PD-1 blockade.

Original languageEnglish
Pages (from-to)4081-4094
Number of pages14
JournalBlood Advances
Volume3
Issue number23
DOIs
Publication statusPublished - Dec 10 2019

ASJC Scopus subject areas

  • Hematology

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