BACKGROUND

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are limited by immune-related adverse events (irAEs). This study aimed to assess peripheral T cell profiles to identify irAEs biomarkers and construct predictive models.

METHODS

In our study, we enrolled and followed 51 gastrointestinal cancer patients receiving anti-PD-1/PD-L1 therapies, with 22 developed irAEs (AE) and 29 didn't (NAE). We examined their peripheral blood using Olink technology, RNA-seq, and flow cytometry to explore the immunological characteristics of their circulating environment before and after early stages of ICIs treatment.

RESULTS

Our study discovered after early stages of ICIs treatment, a stronger upregulation of T cell activation genes, particularly Tfh-associated genes, was observed in AE patients. Flow cytometry result confirmed that AE patients exhibited elevated CD4CXCR5ICOS cells (p<0.01), CD4CXCR5ICOS cells (p<0.05) and Th1/Th2 ratio (p<0.05) after early stages. At baseline, AE patients had higher levels of serum inflammatory proteins including IL-12β, IL-15RA and CXCL9 (p<0.05). Higher peripheral Tfh (p<0.05), Tph (p<0.001) were also observed in the baseline flow cytometry result of AE patients compared to NAE patients. Based on these findings, predictive models for both irAEs and grade 2-4 irAEs were established, demonstrating good discriminatory ability.

CONCLUSION

This study demonstrates that high-dimensional immune profiling can uncover novel blood-based immune signatures associated with the risk and mechanism of severe irAEs are effective biomarkers for predicting irAEs at both baseline and early stages of ICIs treatment.