Tumor-associated CD8T cell tolerance induced by erythroid progenitor cells.

INTRODUCTION

CD8T cell tolerance plays an important role in tumor escape. Recent studies have shown that CD45 erythroid progenitor cells (CD45EPCs) generated through splenic extramedullary erythropoiesis suppress tumor immunity. However, the mechanism underlying how CD45EPCs mediate CD8T cell tolerance remains incompletely understood and requires further research.

METHODS

In this study, the antigen-processing abilities of CD45EPCs was verified through both in vitro and in vivo experiments. We have used the method of co-culture in vitro and adoptive transfer experiments in vivo to explore the effects of CD45EPCs on CD8T cell tolerance. RNA-sequencing analysis and blocking experiments were used to evaluate the role of ROS in the CD45EPC mediated tolerance of CD8T cells. Finally, we incorporated uric acid into the adoptive transfer experiments to rescue the CD45EPC mediated tumor-promoting effect.

RESULTS AND DISCUSSION

We found that CD45EPCs take up soluble proteins, present antigenic epitopes on their surface, and induce antigen-specific CD8T cell anergy. In addition, we found that CD45EPC directly nitrates tyrosine within the TCR/CD8 complex via the production of reactive oxygen species and peroxynitrite, preventing CD8 T cells from responding to their specific peptide antigens. Furthermore, uric acid treatment effectively abolished the immunosuppressive effects of CD45EPCs during CD8T cell adoptive transfer, thereby enhancing the anti-tumor efficacy. These results demonstrated that CD8T cell tolerance in tumor-bearing mice is induced by CD45EPCs. The results of this study have direct implications for tumor immunotherapy.