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4793 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

Program: Oral and Poster Abstracts
Session: 701. Experimental Transplantation: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Fundamental Science, Research
Monday, December 11, 2023, 6:00 PM-8:00 PM

Qingxiao Song, MD, PhD1*, Yuankun Zhang2*, Kaniel Cassady, PhD1,3, Qinjian Li4*, Paul J. Martin, MD5 and Defu Zeng, MD2

1Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA
2Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, Beckman Research Institute of City of Hope, Duarte, CA
3Regeneron Pharmaceuticals, Tarrytown, NY
4Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Comprehensive Cancer Center, Duarte, CA
5Fred Hutchinson Cancer Center, Seattle, WA

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

Disclosures: Cassady: Regeneron Pharmaceuticals: Current Employment.

*signifies non-member of ASH