Blockade of PD-L1/CD80 Interactions Augments Function of Activated Donor T Cells Results in Augmenting Gvhd Induced By Donor Naïve CD8+ t Cells and GVL Effect Mediated By Donor Memory CD8+ T Cells

Preventing graft-versus-host disease (GVHD) while preserving graft-versus-leukemia/lymphoma (GVL) activity remains an elusive goal for allogeneic hematopoietic cell transplantation (HCT). It was reported by others that while donor naïve CD8⁺ T cells mediate both GVHD and GVL activity, donor memory CD8⁺ T cells could mediate GVL activity without GVHD. We recently reported that in vivo specific blockade of PD-L1/CD80 interactions augment tumor immunity mediated by memory CD8⁺ T cells (Zhang et al: PNAS 2023). In the current studies, we evaluated the impact of blockade of PD-L1/CD80 on GVHD induced by donor naïve CD8⁺ T cells and GVL activity-mediated by donor memory CD8⁺ T cells. Sorted naïve CD8⁺ T or memory CD8⁺ T cells and TCD-BM cells from C57BL/6 donors were transplanted into lethal TBI-conditioned BALB/c recipients with or without bearing ALL cancer cells. 4 days after HCT, the recipients were injected I.P. with anti-PD-L1 mAb (43H12) that specifically blocks PD-L1/CD80 interactions without inferring PD-L1/PD-1 interactions or control IgG. We observed that naïve but not memory CD8⁺ T cells severely infiltrated GVHD target tissues, and the memory CD8⁺ T cells expanded mainly in the lymphoid tissues. In vivo blockade of PD-L1/CD80 interactions augmented GVHD induced by the naïve T cells and GVL activity mediated by the memory CD8⁺ T cells. In addition, blockade of PD-L1/CD80 interactions increased production of granzyme B and inflammatory cytokines (IFN-g and TNF-α) of activated donor CD8⁺ T cells. Since cytolytic activity of effector CD8⁺ T cell is reported to be associated with its metabolic fitness, we evaluated the effect of blockade PD-L1/CD80 interactions on metabolism of alloreactive donor CD8⁺ T cells. And blockade of the interactions enhanced the fitness of mitochondria, as indicated by electronic microscopy analysis. The blockade also increased ECAR, OCR, and ATP production of the activated CD8⁺ T cells, with increased influx of glucose and fatty acids; and the blockade augmented mitophagy of the activated CD8⁺ T cells, as indicated by reducing mitochondria mass and dysfunctional mitochondria in the CD8⁺ T cells. The results indicate that 1) PD-L1/CD80 interactions play an important role in regulating the mitochondria function of activated alloreactive CD8⁺ T cells; 2) Blockade of PD-L1/CD80 interactions can augment GVL activity mediated by donor memory T cells without augmenting GVHD. This is different from blockade of PD-L1/PD-1 interactions that resulted in lethal GVHD.

*Zhang and Song are co-first authors of this abstract