Peritransplant glucocorticoids redistribute donor T cells to the bone marrow and prevent relapse after haploidentical SCT
Takayuki Inoue, Motoko Koyama, Katsuji Kaida, Kazuhiro Ikegame, Kathleen S. Ensbey, Luke Samson, Shuichiro Takahashi, Ping Zhang, Simone A. Minnie, Satoshi Maruyama, Shinichi Ishii, Takashi Daimon, Takahiro Fukuda, Hirohisa Nakamae, Takahide Ara, Yumiko Maruyama, Ken Ishiyama, Tatsuo Ichinohe, Yoshiko Atsuta, Bruce R. Blazar, Scott N. Furlan, Hiroyasu Ogawa, Geoffrey R. Hill
Takayuki Inoue, Motoko Koyama, Katsuji Kaida, Kazuhiro Ikegame, Kathleen S. Ensbey, Luke Samson, Shuichiro Takahashi, Ping Zhang, Simone A. Minnie, Satoshi Maruyama, Shinichi Ishii, Takashi Daimon, Takahiro Fukuda, Hirohisa Nakamae, Takahide Ara, Yumiko Maruyama, Ken Ishiyama, Tatsuo Ichinohe, Yoshiko Atsuta, Bruce R. Blazar, Scott N. Furlan, Hiroyasu Ogawa, Geoffrey R. Hill
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Research Article Transplantation

Peritransplant glucocorticoids redistribute donor T cells to the bone marrow and prevent relapse after haploidentical SCT

Abstract

Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes, with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities, but it typically requires intensive immunosuppression with posttransplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here, we demonstrate in preclinical models that glucocorticoid administration from days –1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the BM, promoting donor T cell residency. This results in significant reductions in GVHD while promoting potent GVL effects; relapse in recipients receiving glucocorticoids, vehicle, or PT-Cy was 12%, 56%, and 100%, respectively. Intriguingly, patients with acute myeloid leukemia not in remission who received unmanipulated haplo-SCT and peritransplant glucocorticoids also had an unexpectedly low relapse rate at 1 year (32%; 95% CI, 18%–47%) with high overall survival at 3 years (58%; 95% CI, 38%–74%). These data highlight a potentially simple and effective approach to prevent relapse in patients with otherwise incurable leukemia that could be studied in prospective randomized trials.

Authors

Takayuki Inoue, Motoko Koyama, Katsuji Kaida, Kazuhiro Ikegame, Kathleen S. Ensbey, Luke Samson, Shuichiro Takahashi, Ping Zhang, Simone A. Minnie, Satoshi Maruyama, Shinichi Ishii, Takashi Daimon, Takahiro Fukuda, Hirohisa Nakamae, Takahide Ara, Yumiko Maruyama, Ken Ishiyama, Tatsuo Ichinohe, Yoshiko Atsuta, Bruce R. Blazar, Scott N. Furlan, Hiroyasu Ogawa, Geoffrey R. Hill

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Figure 8

Glucocorticoids induce changes in migration and adhesion molecules to promote migration into the BM.

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Glucocorticoids induce changes in migration and adhesion molecules to pr...
(A) Bulk RNA-Seq of (in vivo CD45 labeled) circulating CD8+ TEM T cells in the BM at day 5 after BMT. Top differentially expressed genes (rows) in glucocorticoid-treated versus control animals (columns). Shown are the row-scaled data, which were subject to variance stabilized transformation. (B) CXCR4 expression on circulating TEM and TCM in the BM (n = 4 per group). (C) CXCL12 expression on BM CD45–CD31–TER119–Sca-1+ mesenchymal stromal cells (MSCs) at day 5 after BMT (n = 10–15 per group from 2 experiments). (D) Representative histogram plots of integrin α4 and β1 expression on donor CD8+ T cells in the BM at day 5. (E) Quantification of D. Results are combined from 3 experiments (n = 11 per group). (F and G) Representative histogram plots of VCAM-1 expression on MSCs (F) and CD45neg CD31+ TER119neg BM endothelial cells at day 5 after BMT and quantification (G) (n = 10 per group from 2 experiments). *P < 0.05; **P < 0.01; ***P < 0.001. Results are combined from 2–3 experiments. All quantified data are presented as mean ± SEM. Student’s t test with Welch’s modification.