Mammadli Mahinbanu, Harris Rebecca, Mahmudlu Sara, Verma Anjali, May Adriana, Dhawan Rohan, Waickman Adam T, Sen Jyoti Misra, August Avery, Karimi Mobin
Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Biomedical Research Center, National Institute on Aging-National Institutes of Health, 08C218, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Cancers (Basel). 2021 Jul 28;13(15):3798. doi: 10.3390/cancers13153798.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most widely applied forms of adoptive immunotherapy for the treatment of hematological malignancies. Detrimental graft-versus-host disease (GVHD), but also beneficial graft-versus-leukemia (GVL) effects occurring after allo-HSCT are largely mediated by alloantigen-reactive donor T cells in the graft. Separating GVHD from GVL effects is a formidable challenge, and a greater understanding of donor T cell biology is required to accomplish the uncoupling of GVHD from GVL. Here, we evaluated the role of β-catenin in this process. Using a unique mouse model of transgenic overexpression of human β-catenin () in an allo-HSCT model, we show here that T cells from mice did not cause GVHD, and surprisingly, T cells maintained the GVL effect. Donor T cells from mice exhibited significantly lower inflammatory cytokine production and reduced donor T cell proliferation, while upregulating cytotoxic mediators that resulted in enhanced cytotoxicity. RNA sequencing revealed changes in the expression of 1169 genes for CD4, and 1006 genes for CD8 T cells involved in essential aspects of immune response and GVHD pathophysiology. Altogether, our data suggest that β-catenin is a druggable target for developing therapeutic strategies to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.
异基因造血干细胞移植（allo-HSCT）是治疗血液系统恶性肿瘤最广泛应用的过继性免疫疗法之一。allo-HSCT后出现的有害移植物抗宿主病（GVHD）以及有益的移植物抗白血病（GVL）效应在很大程度上由移植物中同种抗原反应性供体T细胞介导。将GVHD与GVL效应分离是一项艰巨的挑战，需要更深入了解供体T细胞生物学才能实现GVHD与GVL的解偶联。在此，我们评估了β-连环蛋白在这一过程中的作用。在allo-HSCT模型中使用独特的人β-连环蛋白转基因过表达小鼠模型，我们在此表明来自小鼠的T细胞不会引起GVHD，而且令人惊讶的是，小鼠T细胞维持了GVL效应。来自小鼠的供体T细胞表现出显著更低的炎性细胞因子产生以及供体T细胞增殖减少，同时上调细胞毒性介质，导致细胞毒性增强。RNA测序揭示了参与免疫反应和GVHD病理生理学关键方面的1169个CD4基因以及1006个CD8 T细胞基因表达的变化。总之，我们的数据表明β-连环蛋白是开发治疗策略的可药物作用靶点，以在allo-HSCT治疗后减少GVHD同时保留有益的GVL效应。
