# PD‐L1 Promotes Immunological Tolerance and Enhances Visual Protection of hESC‐RPE Grafts in Retinal Degeneration

## TL;DR

This study shows that overexpressing PD-L1 in hESC-RPE cells improves their survival and visual protection in retinal degeneration models, offering a new strategy for AMD therapy.

## Contribution

The study introduces PD-L1 overexpression as a novel method to enhance hESC-RPE graft survival without MHC gene deletion.

## Key findings

- PD-L1-expressing hESC-RPE grafts showed higher survival and reduced apoptosis in retinal degeneration models.
- Single-cell transcriptomics revealed reduced immune activation and oxidative stress in PD-L1-overexpressing grafts.
- Improved light transduction in host photoreceptors was observed with PD-L1-expressing grafts.

## Abstract

Immune rejection is a major barrier to the successful human embryonic stem cell‐derived retinal pigment epithelial (hESC‐RPE) transplantation for age‐related macular degeneration (AMD). Traditional strategies to mitigate immune rejection involve ablating major histocompatibility complex (MHC) molecules on hESC‐RPE. An alternative approach is immune checkpoint overexpression, avoiding natural killer (NK) cell‐mediated destruction due to MHC‐I deficiency. Our study highlights the benefits of PD‐L1 overexpression without requiring MHC gene deletion, which preserved the immunosuppressive functions of hESC‐RPE on NK cells. In Vivo experiments in retinal degeneration models showed that PD‐L1‐expressing hESC‐RPE grafts exhibited significantly higher survival, reduced apoptosis and enhanced visual protection. Single‐cell transcriptomics revealed reduced immune activation and oxidative stress in PD‐L1‐overexpressing grafts. PD‐L1's protective role was further evidenced by improved light transduction in host photoreceptors. These findings support PD‐L1 overexpression as a promising strategy to improve the efficiency of hESC‐RPE‐based therapy for AMD.

We generated immune‐tolerant mature hESC‐RPE cells by overexpressing PD‐L1. PD‐L1‐expressing hESC‐RPE grafts exhibited significantly higher survival, reduced apoptosis and enhanced visual protection in retinal degeneration models, which presents an alternative target to improve the efficiency of hESC‐RPE‐based therapy for AMD.