Blockade of CD155 and CD276 by Monoclonal Antibodies Fosters Immune Tolerance and Promotes Stable Engraftment of iPSC-Derived Islets in Allogeneic Humanized Mice

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 immune responses. Current immunosuppressive therapies pose significant long-term risks and only partially control alloimmune and autoimmune reactions. Targeted immunomodulation using monoclonal antibodies is a safer, more precise alternative. Here, we explored the impacts of blocking CD276 (B7-H3) and CD155 (PVR), activating ligands involved in immune recognition and regulation, on the survival and <i>in vivo</i> 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. In addition, CD155 blockade increased PD-1 levels on activated CD8⁺ T cells and significantly enhanced regulatory T cell (Treg) expansion and function, thereby promoting graft tolerance. Combined treatment prolonged engraftment and facilitated the maturation of EPs into functional, insulin-secreting cells, as indicated by increased human C-peptide levels and glucose responsiveness 4 weeks post-transplantation. Our findings highlight CD276/CD155 blockade as a novel immunomodulatory strategy to support tolerance and the functional maturation of iPSC-derived pancreatic grafts in T1D.