Pharmacologic inhibition of PKCα and PKCθ prevents GVHD while preserving GVL activity in mice

Allogeneic hematopoietic cell transplantation (HCT) is the most effective therapy for hematopoietic malignancies through T-cell-mediated graft-vs-leukemia (GVL) effects but often leads to severe graft-vs-host disease (GVHD). Given that protein kinase C theta (PKC theta), in cooperation with PKC alpha, is essential for T-cell signaling and function, we have evaluated PKC theta and PKCa as potential therapeutic targets in allogeneic HCT using genetic and pharmacologic approaches. We found that the ability of PKC alpha(-/-)/theta(-/-) donor T cells to induce GVHD was further reduced compared with PKC theta(-/-) T cells in relation with the relevance of both isoforms to allogeneic donor T-cell proliferation, cytokine production, and migration to GVHD target organs. Treatment with a specific inhibitor for both PKC theta and PKCa impaired donor T-cell proliferation, migration, and chemokine/cytokine production and significantly decreased GVHD in myeloablative preclinical murine models of allogeneic HCT. Moreover, pharmacologic inhibition of PKC theta and PKCa spared T-cell cytotoxic function and GVL effects. Our findings indicate that PKCa and theta contribute to T-cell activation with overlapping functions essential for GVHD induction while less critical to the GVL effect. Thus, targeting PKCa and PKC theta signaling with pharmacologic inhibitors presents a therapeutic option for GVHD prevention while largely preserving the GVL activity in patients receiving HCT.