ER Stress Sensor PERK Regulates T-Cell Allogeneic and Anti-Tumor Responses Distinctly

Unfolded protein response (UPR) is a conserved adaptive signaling pathway that serves to manage the endoplasmic reticulum (ER) stress in response to the accumulation of misfolded and unfolded proteins. It is known that tumor cells take advantage of UPR to thrive in the adverse tumor microenvironment and limit anti-tumor immunity. However, it is much less understood how UPR mediators regulate T cell response to allogeneic antigens. In the current study, we investigated how UPR mediators regulate T cell mediated graft-versus-host (GVH) and graft-versus-leukemia (GVL) responses after hematopoietic cell transplantation (HCT).

To determine the contribution of two major UPR mediators, PERK and XBP-1, on T cell-mediated GVHD development and GVL activity, we used multiple preclinical murine allo-HCT models and T cell-specific PERK (PERK^flox/floxCD4cre⁺) or XBP-1 (XBP-1^flox/flox CD4cre⁺) deficient mice as donors. We found that T cells deficient for PERK but not XBP-1 significantly reduced the pathogenicity in the induction of aGVHD. However, PERK deficiency in T cells did not impair T cell anti-tumor activity and thus preserved the GVL activity. It has been reported that PERK repressed the mitochondrial respiration and T cell activation under tumor microenvironment through PERK-CHOP signaling. Interestingly, we observed that PERK-deficient T cells reduced proliferation, activation, and metabolism upon allogeneic stimulation. CHOP expression was increased in T cells without PERK signals after allogeneic stimulation, in contrast to those after polyclonal anti-CD3 stimulation. To further define underlying mechanisms, we performed RNA sequencing assays on the T cells after allogeneic or polyclonal stimulation. We found that ER-associated protein degradation (ERAD) is increased in PERK-deficient T cells only after allogeneic stimulation. Furthermore, inhibition of ERAD with kifunensine essentially reversed T-cell allo-response in the absence of PERK. For translational purposes, we tested the ER stress inhibitor, tauroursodeoxycholic acid (TUDCA), in murine GVH/GVL models, and found that TUDCA effectively ameliorated the development of aGVHD in a PERK-dependent manner.

In conclusion, PERK plays a distinct role in regulating T cell allogeneic versus anti-tumor response. Inhibition of PERK results in ameliorated aGVHD while preserving the GVL activity in murine models of allo-HCT. Our finding reveals a novel insight how ER stress sensor regulates T cell mediated GVH and GVL response and provides a rationale in targeting UPR for improving the efficiency of allo-HCT for blood cancer patients.

No relevant conflicts of interest to declare.