Targeting Aurora kinase A and JAK2 prevents GVHD while maintaining Treg and antitumor CTL function.

Graft-versus-host disease (GVHD) is a leading cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation. T cell costimulation by CD28 contributes to GVHD, but prevention is incomplete when targeting CD28, downstream mammalian target of rapamycin (mTOR), or Aurora A. Likewise, interleukin-6 (IL-6)–mediated Janus kinase 2 (JAK2) signaling promotes alloreactivity, yet JAK2 inhibition does not eliminate GVHD. We provide evidence that blocking Aurora A and JAK2 in human T cells is synergistic in vitro, prevents xenogeneic GVHD, and maintains antitumor responses by cytotoxic T lymphocytes (CTLs). Aurora A/JAK2 inhibition is immunosuppressive but permits the differentiation of inducible regulatory T cells (iTregs) that are hyperfunctional and CD39 bright and efficiently scavenge adenosine triphosphate (ATP). Increased iTreg potency is primarily a function of Aurora A blockade, whereas JAK2 inhibition suppresses T helper 17 (TH17) differentiation. Inhibiting either Aurora A or JAK2 significantly suppresses TH1 T cells. However, CTL generated in vivo retains tumor-specific killing despite Aurora A/JAK2 blockade. Thus, inhibiting CD28 and IL-6 signal transduction pathways in donor T cells can increase the Treg/Tconv ratio, prevent GVHD, and preserve antitumor CTL.

移植物抗宿主病（GVHD）是异基因造血细胞移植后非复发死亡的主要原因。CD28对T细胞的共刺激作用会促进GVHD，但针对CD28、雷帕霉素靶蛋白（mTOR）下游靶点或极光激酶A（Aurora A）进行预防时效果并不完全。同样，白细胞介素 - 6（IL - 6）介导的Janus激酶2（JAK2）信号传导会促进同种异体反应性，但抑制JAK2并不能消除GVHD。我们提供的证据表明，在人T细胞中阻断极光激酶A和JAK2在体外具有协同作用，可预防异种GVHD，并维持细胞毒性T淋巴细胞（CTLs）的抗肿瘤反应。极光激酶A/JAK2抑制具有免疫抑制作用，但允许诱导性调节性T细胞（iTregs）分化，这些细胞功能亢进且CD39表达明亮，能有效清除三磷酸腺苷（ATP）。iTreg效力的增强主要是极光激酶A阻断的作用，而JAK2抑制可抑制辅助性T细胞17（TH17）的分化。抑制极光激酶A或JAK2均可显著抑制TH1 T细胞。然而，尽管存在极光激酶A/JAK2阻断，体内产生的CTL仍保留肿瘤特异性杀伤能力。因此，抑制供体T细胞中的CD28和IL - 6信号转导通路可提高调节性T细胞/常规T细胞（Treg/Tconv）的比例，预防GVHD，并保留抗肿瘤的CTL。