Tumor-associated CD8⁺T cell tolerance induced by erythroid progenitor cells

CD8⁺T cell tolerance plays an important role in tumor escape. Recent studies have shown that CD45⁺ erythroid progenitor cells (CD45⁺EPCs) generated through splenic extramedullary erythropoiesis suppress tumor immunity. However, the mechanism underlying how CD45⁺EPCs mediate CD8⁺T cell tolerance remains incompletely understood and requires further research.

In this study, the antigen-processing abilities of CD45⁺EPCs 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 CD45⁺EPCs on CD8⁺T cell tolerance. RNA-sequencing analysis and blocking experiments were used to evaluate the role of ROS in the CD45⁺EPC mediated tolerance of CD8⁺T cells. Finally, we incorporated uric acid into the adoptive transfer experiments to rescue the CD45⁺EPC mediated tumor-promoting effect.

We found that CD45⁺EPCs take up soluble proteins, present antigenic epitopes on their surface, and induce antigen-specific CD8⁺T cell anergy. In addition, we found that CD45⁺EPC 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 CD45⁺EPCs during CD8⁺T cell adoptive transfer, thereby enhancing the anti-tumor efficacy. These results demonstrated that CD8⁺T cell tolerance in tumor-bearing mice is induced by CD45⁺EPCs. The results of this study have direct implications for tumor immunotherapy.