PD-L1’s Role in Preventing Alloreactive T Cell Responses Following Hematopoietic and Organ Transplant

Abstract

Over the past decade, Programmed Death-Ligand 1 (PD-L1) has emerged as a prominent target for cancer immunotherapies. However, its potential as an immunosuppressive therapy has been limited. In this review, we present the immunological basis of graft rejection and graft-versus-host disease (GVHD), followed by a summary of biologically relevant molecular interactions of both PD-L1 and Programmed Cell Death Protein 1 (PD-1). Finally, we present a translational perspective on how PD-L1 can interrupt alloreactive-driven processes to increase immune tolerance. Unlike most current therapies that block PD-L1 and/or its interaction with PD-1, this review focuses on how upregulation or reversed sequestration of this ligand may reduce autoimmunity, ameliorate GVHD, and enhance graft survival following organ transplant.

Exploring Costimulatory Blockade-Based Immunologic Strategies in Transplantation: Are They a Promising Immunomodulatory Approach for Organ and Vascularized Composite Allotransplantation?

“…Utilizing PD-L1 as an immunomodulatory approach presents a potential strategy for preventing graft-versus-host disease (GVHD) as well as preventing transplant rejection. However, the function of this pathway in a clinical context remains to be precisely determined [ 87 ].…”

“…This type of tumor frequently arises as a complication in patients who are chronically immunosuppressed following a transplant. Cemiplimab represents a promising therapeutic option that can be incorporated into the treatment regimen for transplant patients requiring ongoing immunosuppression who develop this type of skin malignancy [ 87 , 158 ].…”

“…Existing research has largely concentrated on inhibiting PD-L1 to prevent immunosuppression, but augmenting PD-L1 activity could be a beneficial strategy for mitigating destructive immune responses. Further research is essential to fully comprehend the implications of increased PD-L1 expression and its availability in treating GVHD and autoimmune diseases, and in the context of organ transplantation, potentially promoting immune tolerance [ 87 , 88 ]. Studies indicate that enhanced PD-L1 expression in GVHD models can improve survival rates and decrease the secretion of pro-inflammatory cytokines.…”

“…Similarly, in the context of organ transplantation, activating PD-L1 has been associated with extended graft survival and lower rejection rates. In models of autoimmune diseases, elevated PD-L1 expression has been linked to slowed disease progression and reduced tissue damage [ 87 ].…”

Regulation of Treg cells by cytokine signaling and co-stimulatory molecules

“…Amarnath et al (213) found that Tregs could promote the generation of bone marrow DCs and reduce their ability to stimulate the generation of efficient T cells in GvHD. Tregs have high surface expression levels of PD-L1, which can bind to PD-L1 of DCs, thus inhibiting the activation of T cells and alleviating GvHD (214,215). In addition, Tregs can express inhibitory molecules (e.g.…”