Granzyme B Contributes to the Optimal Graft-Versus-Tumor Effect Mediated by Conventional CD4⁺ T Cells

Granzyme B (GzmB) is a key cytotoxic molecule utilized by T cells to kill pathogen-infected cells or transformed tumor cells. Previous studies using allogeneic hematopoietic cell transplantation (allo-HCT) murine models showed that GzmB is required for CD8⁺ T cells to cause graft-versus-host disease (GVHD). However, our recent study demonstrated that GzmB-mediated damage of CD8⁺ T cells diminished their graft-versus-tumor (GVT) activity. In this study, we examined the role of GzmB in GVT effect mediated by conventional CD4⁺CD25^- T cells (CD4⁺ Tcon). GzmB^-/-CD4⁺ Tcon cells exhibited decreased GVT activity compared to wild-type (WT) CD4⁺ Tcon cells, suggesting that GzmB is required for the optimal GVT activity of CD4⁺ Tcon cells. On the other hand, GzmB^-/- CD4⁺CD25⁺ regulatory T cells were as suppressive as WT regulatory T cells in suppressing GVT activity, which is consistent with our previous report showing that GzmB is not required for regulatory T cell-mediated suppression of GVHD. These results demonstrate that GzmB causes opposite impacts on GVT effect mediated by CD4⁺CD25^- versus CD8⁺ T cells. Interestingly, GzmB^-/- total T cells exhibited GVT activity equivalent to that of WT total T cells, suggesting that the opposite impacts of GzmB on the GVT effect of CD4⁺CD25^- versus CD8⁺ T cells may neutralize each other, which can only be observed when an individual T cell subset is examined. Importantly, these differential roles suggest that targeting GzmB in selective T cell subsets may have the potential to enhance the beneficial GVT effect.