The FSTL1-DIP2A axis is a significant biomarker for predicting anti-PD1 therapeutic efficacy in advanced gastric cancer

Follistatin-like 1 (FSTL1) has been demonstrated to be a key molecule in cancer intractability associated with immune exhaustion and dysfunction, and increased expression of FSTL1 and its receptor DIP2A in tumor tissues has also been reported as a significant poor prognostic factor in various types of cancer, including gastric cancer (GC). However, the relationship between FSTL1/DIP2A levels, especially those in the peripheral circulation, and clinical outcomes in anti-PD1/PDL1 therapy remains to be elucidated in clinical practice. We collected peripheral blood collected from patients with advanced GC before and after nivolumab monotherapy, and analyzed for FSTL1 by ELISA, and for DIP2A⁺ cells by flow cytometry, followed by statistical analysis of association with patient prognosis. High FSTL1 levels at baseline were significantly associated with shorter progression-free survival (PFS) and overall survival (OS). Patients with high levels of DIP2A⁺ subsets in CD11b⁺ myeloid cells, CD3⁺ T cells, and CD56⁺ NK cells both before and after treatment showed significantly shorter PFS and OS as compared to patients with low levels. Combination of low baseline levels of both FSTL1 and DIP2A⁺ cells identified patients with long-term survival, known as durable responders. These data suggest that high baseline levels of both FSTL1 and DIP2A⁺ cells in peripheral blood are significant poor prognostic factors for nivolumab therapy for advanced GC. Targeting the FSTL1-DIP2A axis may be a promising strategy to improve clinical outcomes in GC as a biomarker to predict anti-PD1/PDL1 therapeutic efficacy more accurately.