# Targeting the pentose phosphate pathway mitigates graft-versus-host disease by rewiring alloreactive T cell metabolism

## TL;DR

Blocking a key enzyme in T cell metabolism reduces dangerous immune reactions after transplants without harming the anti-cancer effect.

## Contribution

Identifying 6PGD in the pentose phosphate pathway as a novel therapeutic target for graft-versus-host disease.

## Key findings

- Donor T cell deficiency in 6PGD reduced graft-versus-host disease severity and mortality in mice.
- Pharmacological PPP inhibition with 6AN reduced GvHD severity while preserving anti-tumor activity.
- PPP blockade halted T cell proliferation without causing cell death.

## Abstract

Glycolysis fuels cytotoxic allogeneic T cells in acute graft-versus-host disease (aGvHD), but the downstream role of glucose metabolism in modulating aGvHD remains unclear. Targeting glycolysis or glucose receptors is toxic. Therefore, we explored alternative glucose-dependent pathways, focusing on the pentose phosphate pathway (PPP). Single-cell RNA sequencing revealed PPP upregulation in allogeneic T cells during allogeneic hematopoietic cell transplantation (allo-HCT). We showed that donor T cell deficiency in 6-phosphogluconate dehydrogenase (6PGD), the second rate-limiting enzyme in the PPP, significantly reduced aGvHD severity and mortality in murine models. Functional assays demonstrated that PPP blockade led to proliferation arrest without inducing apoptosis. PPP blockade shifted T cell metabolism away from T cell dependency on glycolysis for rapid T cell proliferation. Pharmacological inhibition of the PPP through 6PGD blockade with 6-aminonicotinamide (6AN) effectively reduced aGvHD severity, like donor 6PGD-deficient T cells in an allogeneic aGvHD model. Similarly, 6AN reduced xenogeneic GvHD lethality. 6PGD inhibition preserved the graft-versus-tumor (GvT) effect, with the generation of a small subset of granzyme Bhi effector T cells with potent antitumor activity. These findings highlight the PPP as a key regulator of allogeneic T cell proliferation and differentiation and identify 6PGD as a promising therapeutic target to mitigate aGvHD severity while preserving beneficial GvT effects.

After blood stem cell transplants, T cells change metabolism. Blocking a key enzyme, 6PGD, significantly lessens graft-versus-host disease severity without losing the beneficial anti-tumor response.