Dual GLP-1R agonist and anti-IL-17A therapy suppresses obesity-driven leukemia in PTPN11-mutant mice

The escalating global prevalence of obesity is increasingly linked to various cancers, including hematopoietic malignancies. However, the precise mechanisms by which obesity influences mutation-driven myeloid leukemias, such as those involving PTPN11 (Shp2) mutations, remain poorly understood. Current standard-of-care treatments for myeloid leukemias often face challenges, particularly in high-risk obese patients where metabolic inflammation can exacerbate disease progression. Identifying novel therapeutic targets that address this metabolic-immune axis is crucial to improve outcomes for these patients. This research investigates the roles of IL-17A and GLP-1R signaling in bridging obesity with leukemogenesis.

Researchers first analyzed UK Biobank data from over 440,000 individuals to identify correlations between obesity traits, type 2 diabetes, plasma IL-17A, GLP-1R expression, and myeloid malignancy risk. Subsequently, they established an in vivo model by transplanting PTPN11 (Shp2E76K/+) mutant hematopoietic stem/progenitors into obese mice. This model allowed for the study of obesity's impact on leukemogenesis. The therapeutic intervention involved dual therapy with an anti-IL-17A antibody and a GLP-1R agonist, administered to the obese, leukemic mice. Primary endpoints included leukemic burden, myeloid cell expansion, lipid metabolic rewiring, IL-17A activation, M2-like tumor-associated macrophage (TAM) accumulation, T-cell exhaustion, and antigen presentation.

Analysis of UK Biobank data revealed that obesity traits, including elevated BMI and waist-to-hip ratio, were significantly associated with type 2 diabetes, increased plasma IL-17A, reduced GLP-1R expression, and a heightened risk of myeloid malignancies. In the preclinical mouse model, transplantation of PTPN11 (Shp2E76K/+) mutant hematopoietic stem/progenitors into obese mice demonstrated that metabolic inflammation markedly accelerated leukemogenesis. This acceleration was characterized by myeloid cell expansion, lipid metabolic rewiring, IL-17A activation, and accumulation of M2-like tumor-associated macrophages (TAMs), alongside T-cell exhaustion and impaired antigen presentation. Importantly, the dual therapy with an anti-IL-17A antibody and a GLP-1R agonist effectively reversed these detrimental effects. > The combined treatment significantly reduced M2-like TAMs, restored Ciita-dependent antigen presentation, reactivated Tyk2-mediated IFNγ signaling, and re-established robust T-cell responses, ultimately leading to a substantial reduction in leukemic burden.