TY - JOUR
T1 - Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses
AU - Thangavelu, Govindarajan
AU - Wang, Chao
AU - Loschi, Michael
AU - Saha, Asim
AU - Osborn, Mark J.
AU - Furlan, Scott N.
AU - Aoyama, Kazutoshi
AU - McDonald-Hyman, Cameron
AU - Aguilar, Ethan G.
AU - Janesick, Amanda S.
AU - Chandraratna, Roshantha A.
AU - Refaeli, Yosef
AU - Panoskaltsis-Mortari, Angela
AU - MacDonald, Kelli P.
AU - Hill, Geoffrey R.
AU - Zeiser, Robert
AU - Maillard, Ivan
AU - Serody, Jonathan S.
AU - Murphy, William J.
AU - Munn, David H.
AU - Blumberg, Bruce
AU - Brown, Chrysothemis
AU - Kuchroo, Vijay
AU - Kean, Leslie S.
AU - Hippen, Keli L.
AU - Noelle, Randolph J.
AU - Blazar, Bruce R.
N1 - Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/2/25
Y1 - 2021/2/25
N2 - The nuclear receptor (NR) subclass, retinoid X receptors (RXRs), exert immunomodulatory functions that control inflammation and metabolism via homodimers and heterodimers, with several other NRs, including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers, but not heterodimers. In this study, in vivo IRX4204 compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T-cell proliferation, reducing T-helper 1 differentiation, and promoting regulatory T-cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating proinflammatory pathways. In vitro, inducible Treg differentiation from naive CD4+ T cells was enhanced by IRX4204. In vivo, IRX4204 increased the conversion of donor Foxp3− T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage-tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrated that IRX4204 supports Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T-cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be a novel approach to preventing acute GVHD in the clinic. Key Points: • A novel RXR agonist attenuates acute GVHD, while retaining graft-versus-leukemia responses. • The RXR agonist enhances Treg generation and stabilizes Foxp3, even in a highly inflammatory environment.
AB - The nuclear receptor (NR) subclass, retinoid X receptors (RXRs), exert immunomodulatory functions that control inflammation and metabolism via homodimers and heterodimers, with several other NRs, including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers, but not heterodimers. In this study, in vivo IRX4204 compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T-cell proliferation, reducing T-helper 1 differentiation, and promoting regulatory T-cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating proinflammatory pathways. In vitro, inducible Treg differentiation from naive CD4+ T cells was enhanced by IRX4204. In vivo, IRX4204 increased the conversion of donor Foxp3− T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage-tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrated that IRX4204 supports Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T-cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be a novel approach to preventing acute GVHD in the clinic. Key Points: • A novel RXR agonist attenuates acute GVHD, while retaining graft-versus-leukemia responses. • The RXR agonist enhances Treg generation and stabilizes Foxp3, even in a highly inflammatory environment.
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U2 - 10.1182/blood.2020005628
DO - 10.1182/blood.2020005628
M3 - Article
C2 - 32976550
AN - SCOPUS:85101370442
SN - 0006-4971
VL - 137
SP - 1090
EP - 1103
JO - Blood
JF - Blood
IS - 8
ER -
