Low-dose IL-2 therapy for immune-related adverse events via Tfh/Treg balance modulation: a prospective cohort and murine model study

Immune-related adverse events (irAEs) are associated with anti-PD-1/PD-L1 therapy in gastrointestinal cancers. Altered phenotypes and frequencies of T cell subsets play a critical role in irAEs. This study characterized the Tfh/Treg balance in irAEs patients and assessed the efficacy of LDIL-2 therapy in mouse models. A prospective study evaluating the immunological characteristics of 26 gastrointestinal cancer patients through both cellular and transcriptomic analyses before and after anti-PD-1/PD-L1 therapy was performed. Patients were categorized into two groups: the AE group (patients who developed irAEs during the follow-up period) and the NAE group (patients who did not). Meanwhile, MRL/MpJ-Fas lpr mice, a lupus mouse model, and tumor-bearing C57BL/6 J mice were used to evaluate the efficacy of LDIL-2 in treating anti-PD-L1 induced irAEs and its impact on antitumor effectiveness. Our study discovered that in AE patients, Tfh-related genes were significantly upregulated during the early stages of anti-PD-1/PD-L1 therapy ( IL-21 : p < 0.01; PDCD1 : p < 0.05), whereas the upregulation of Treg-related genes was less pronounced compared to Tfh-related genes. This distinction was not observed in NAE patients. Flow cytometry results further confirmed a substantial increase in the Tfh/Treg ratio in AE patients during the early stages of therapy (p < 0.001), a phenomenon absent in NAE patients. In MRL/MpJ-Fas lpr mice, anti-PD-L1 therapy induced a shift in the Tfh/Treg ratio, along with severe organ inflammatory lesions and elevated anti-dsDNA antibody levels. In contrast, LDIL-2 treated mice maintained a balanced Tfh/Treg ratio, exhibiting significantly fewer organ inflammatory lesions and reduced anti-dsDNA production. Furthermore, in tumor-bearing mice, LDIL-2 did not impair the antitumor efficacy of anti-PD-L1 therapy. Our study underscores the importance of Tfh/Treg balance in the development of irAEs and demonstrates the potential of LDIL-2 as a therapeutic option for irAEs, providing a promising alternative to traditional immunosuppressive therapies for managing irAEs.