HIF-1α inhibitor echinomycin reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect.
Acute graft-versus-host disease (aGVHD) remains a major obstacle against favorable clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). T helper cells including Th17 play key roles in aGVHD pathogenesis. Donor regulatory T cell (Tregs) adoptive therapy reduces aGVHD without weakening graft-versus-leukemia effect (GVL) in both mouse and human, although the purification and ex vivo expansion of Tregs in clinical scenarios remain costly and technically demanding. Hypoxia-inducible factor 1 alpha (HIF-1α) is a key molecule switch that attenuates Treg but promotes Th17 development. However, whether pharmacological inhibition of HIF-1α reduces aGVHD via increasing Treg development and diminishing Th17 responses remains unexplored.



By using alloantigen-specific mixed lymphocyte culture and murine models of aGVHD and GVL, we evaluated the impacts of HIF-1α inhibition by echinomycin on the alloantigen-specific CD4 T cell responses ex vivo, as well as on aGVHD and GVL effect following allo-HSCT.



Ex vivo echinomycin treatment resulted in increased number of Tregs in the culture as well as reduced alloantigen-specific Th17 and Th1 responses. In vivo echinomycin treatment reduced GVHD scores and prolonged survival of mice following allo-HSCT, which is associated with increased number of donor Tregs and reduced number of Th17 and Th1 in lymphoid tissues. In murine model of leukemia, echinomycin treatment preserved GVL effect and prolonged leukemia free survival following allo-HSCT.



Echinomycin treatment reduces aGVHD and preserves GVL effect via increasing donor Treg development and diminishing alloantigen-specific Th17 and Th1 responses following allo-HSCT, presumably via direct inhibition of HIF-1α that results in preferential Treg differentiation during alloantigen-specific CD4 T cell responses. These findings highlight pharmacological inhibition of HIF-1α as a promising strategy in GVHD prophylaxis.
MDCL-4084, Department of Pathology & Molecular Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, L8S4K1, Canada. yaoy15@mcmaster.ca.|Department of Hematology, Shenzhen People's Hospital, 1017 Dongmen North Road, Shenzhen, 518020, China. yaoy15@mcmaster.ca.
Yushi
0000-0001-6044-8497
Y
Yao
Department of Hematology and Department of Clinical Nutrition, General Hospital of Chinese People's Armed Police Forces, 69 Yong Ding Road, Beijing, 100039, China.
Lei
L
Wang
Department of Hematology, Shenzhen People's Hospital, 1017 Dongmen North Road, Shenzhen, 518020, China.
Jihao
J
Zhou
Department of Hematology, Shenzhen People's Hospital, 1017 Dongmen North Road, Shenzhen, 518020, China. zhangxinyou0518@sina.com.
Xinyou
X
Zhang
D000818:Animals; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D004448:Echinomycin / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy*; D020544:Graft vs Leukemia Effect / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007519:Isoantigens; D004448:Echinomycin
Acute graft-versus-host disease; Echinomycin; Graft-versus-leukemia effect; Hypoxia-inducible factor 1 alpha; Regulatory T cells; Th17 cells