Abstract / Summary
Purpose Radiation enteritis (RE) is a frequent and challenging complication of radiotherapy for abdominal and pelvic malignancies, characterized by intestinal epithelial damage, immune dysregulation, and inflammation. Current treatments are limited by poor efficacy and significant side effects. Radiation-induced DNA damage can generate neoantigens, but their role in RE pathogenesis and therapeutic potential remains unclear. Methods An irradiation-induced RE mouse model was established. The dependency on dendritic cell (DCs) and CD8 + T cells was examined using depletion models. Indel-derived neoantigens were predicted and screened from transcriptomic data using bioinformatics tools (ScanNeo, NetMHCpan 4.1). Immunogenicity of candidate peptides was validated in vivo via prime-boost immunization. Selected candidate neoantigen peptides were administered via daily enema to mice. The pathogenic mechanisms were assessed by body weight, histopathology (H&E), immunohistochemistry (CD4, CD8, TNF-α, RAD51, γH2AX), immunofluorescence (LGR5), flow cytometry, and ELISA. Results In vitro, 7 Gy irradiation promoted CD8 + CD137 + T cell activation and pro-inflammatory cytokine secretion in PBMC co-culture. Depletion of DCs or CD8 + T cells decreased the RE effects, indicating that this immune axis contributes to the RE phenotype. A total of 6 computationally predicted, high-affinity indel-derived candidate peptides (AP1–AP6) were screened. AP2–AP6 demonstrated robust immunogenicity, DC maturation, and CD4 + /CD8 + T cell activation. Enema administration of AP2–AP6 induced only transient weight loss and reduced LGR5 + intestinal stem cells. Continuous enema administration of the candidate peptides induced the pro-inflammatory signature upregulation of TNF-α and IFN-γ both systemically and locally. Conclusions Our findings suggest that radiation-associated indel-derived peptides with in vivo immunogenicity can drive intestinal immune activation and DC-CD8 + T cell-associated inflammation contributes to RE pathogenesis, providing new insight into RE pathogenesis.