Blockade of CD155 and CD276 by monoclonal antibodies fosters immune tolerance and promotes stable engraftment of iPSC-derived islets in allogeneic humanized mice

Abstract

Induced pluripotent stem cell (iPSC)-derived pancreatic islets represent a promising therapeutic approach for restoring insulin independence in type 1 diabetes (T1D). However, their clinical success remains critically dependent on overcoming rejection mediated by innate and adaptive responses. Current immunosuppressive therapies carry significant long-term risks and incompletely control alloimmune and autoimmune reactions. Targeted immunomodulation using monoclonal antibodies offers a safer and more precise alternative. Here, we explored the impact of blocking CD276 (B7-H3) and CD155 (PVR), activating ligands involved in immune recognition and regulation, on the survival and in vivo maturation of iPSC-derived endocrine progenitors (EPs) into functional pancreatic islets. Using a humanized mouse model, we demonstrated that dual blockade of CD276 and CD155 markedly reduced NK cell-mediated graft rejection, prevented CD14+ monocyte activation, and limited overall immune infiltration. Besides, CD155 blockade increased PD-1 levels on activated CD8+ T cells and significantly enhanced regulatory T cell (Treg) expansion and function, promoting graft tolerance. Combined treatment prolonged engraftment and facilitated maturation of EPs into functional insulin-secreting cells, as indicated by increased human c-peptide levels and glucose responsiveness four weeks post-transplantation. Our findings highlight CD276/CD155 blockade as a novel immunomodulatory strategy to support tolerance and functional maturation of iPSC-derived pancreatic grafts in T1D.