16P - Exosomal PD-L1 and lactate predict clinical outcomes of PD-1 blockade combined with chemotherapy in advanced-stage gastric and gastroesophageal junction adenocarcinoma

Background

First-line therapy with PD-1 blockade and chemotherapy is recommended for human epidermal growth factor receptor 2 (HER2)–negative patients with advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC), but the clinical outcomes of this approach is very variable. Predictive biomarkers are thus urgently required, here we investigated the predictive ability of exosomal PD-L1 and lactate levels in advanced GC or GEJC patients.

Methods

This prospective study (RENMIN-221) enrolled 68 advanced GC or GEJC patients receiving first-line PD-1 blockade and standard chemotherapy from January 2022 to March 2023. Exosomes were isolated by ultracentrifugation method from plasma prior to therapy. PD-L1 and lactate levels of the recovered exosomes were determined by enzyme-linked immunosorbent assay (ELISA), and peripheral blood was obtained before each cycle of treatment. The composition of peripheral CD3⁺ T cells, CD4⁺T cells, CD8⁺T cells, regulatory T (CD4⁺CD25⁺CD127^low, Treg) cells, and the expression of their PD-1 were assessed by flow cytometry.

Results

Compared to the responders (CR+PR), exosomal PD-L1 (P=0.014) and lactate (P=0.012) was significantly higher than that of the non-responders (SD+PD) before the treatment. The receiver operating characteristic (ROC) curve showed that the combination of exosomal PD-L1 and lactate best distinguished responders from non-responders (area under the curve [AUC]: 0.787 vs. 0.748 vs. 0.706) among all the parameters tested. Combining predictor lower than -0.274 was associated with a better response to the therapy by ORR (82.1% vs. 30.0%, P<0.001), and mPFS (13.8 vs 5.5 months, P<0.001). Exosomal PD-L1 levels were signifcantly correlated with the frequency of CD8⁺T cells before treatment (P=0.025). And exosomal lactate was associated with less CD8⁺T cells and more Treg cells after treatment, while exosomal PD-L1was associated with more Treg cells and more PD-1⁺ Treg cells after treatment.

Conclusions

Exosomal PD-L1 and lactate levels could predict clinical outcomes, which provide accurate and convenient biomarkers in advanced GC or GEJC patients receiving first-line PD-1 blockade combined with chemotherapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.