Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses

Govindarajan Thangavelu, Chao Wang, Michael Loschi, Asim Saha, Mark J. Osborn, Scott N. Furlan, Kazutoshi Aoyama, Cameron McDonald-Hyman, Ethan G. Aguilar, Amanda S. Janesick, Roshantha A. Chandraratna, Yosef Refaeli, Angela Panoskaltsis-Mortari, Kelli P. MacDonald, Geoffrey R. Hill, Robert Zeiser, Ivan Maillard, Jonathan S. Serody, William J. Murphy, David H. MunnBruce Blumberg, Chrysothemis Brown, Vijay Kuchroo, Leslie S. Kean, Keli L. Hippen, Randolph J. Noelle, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1090-1103
Number of pages14
JournalBlood
Volume137
Issue number8
DOIs
StatePublished - Feb 25 2021

Bibliographical note

Funding Information:
The authors thank Elizabeth Nowak for input. This work was funded by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grants P01 AI056299 and R01 AI034495, and NIH/National Heart, Lung, and Blood Institute grants R01 HL56067 (B.R.B.) and R01 AI091627 (I.M.); Deutsche Forschungsgemeinschaft grants 872/4-1 and SFB1160 TP B09, Deutsche Krebshilfe grant 70113473, Jose-Carreras Leukemia Foundation grant DJCLS 01R/2019 (R.Z); a fellowship from the Canadian Institutes of Health Research (CIHR) (G.T.); and funding from the Leukemia and Lymphoma Society, the Children's Cancer Research Fund, and the KidsFirst Fund (B.R.B.). Conflict-of-interest disclosure: B.R.B. has received remuneration as an advisor to Kamon Pharmaceuticals, Inc, Five Prime Therapeutics Inc, Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeutics and research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences Inc, and Abbvie Inc. B.R.B. is a cofounder of Tmunity. The remaining authors declare no competing financial interests. Roshantha A. Chandraratna died on 8 January 2019.

Funding Information:
This work was funded by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grants P01 AI056299 and R01 AI034495, and NIH/National Heart, Lung, and Blood Institute grants R01 HL56067 (B.R.B.) and R01 AI091627 (I.M.); Deutsche Forschungsgemeinschaft grants 872/4-1 and SFB1160 TP B09, Deutsche Krebshilfe grant 70113473, Jose-Carreras Leukemia Foundation grant DJCLS 01R/2019 (R.Z); a fellowship from the Canadian Institutes of Health Research (CIHR) (G.T.); and funding from the Leukemia and Lymphoma Society, the Children's Cancer Research Fund, and the KidsFirst Fund (B.R.B.).

Publisher Copyright:
© 2021 American Society of Hematology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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