Exosomal PD-L1 and lactate versus tissue PD-L1 as biomarkers for clinical outcomes of PD-1 Blockade plus chemotherapy in metastatic esophagogastric signet ring cell carcinoma.

In this investigator-initiated, prospective, exploratory study, biomarkers predictive of clinical outcomes of first-line immune checkpoint inhibitor (ICI, nivolumab or pembrolizumab) plus XELOX(oxaliplatin and capecitabine) were identified in human epidermal growth factor receptor 2 (HER2)-negative patients with metastatic esophagogastric signet ring cell carcinoma. The findings showed an objective response rate (ORR) of 51.5% and a disease control rate of 86.8%, the median progression-free survival (PFS) for the entire cohort was 6.63 months. PD-L1 expression level in tumor tissues could not identify a high PD-L1 group that significantly benefited from ICI plus XELOX in terms of the ORR and PFS. By contrast, the patients expressing low exosomal PD-L1 or lactate in peripheral blood plasma before treatment initiation demonstrated a significantly increased ORR and prolonged PFS compared to that with high exosomal PD-L1 or lactate, patients with combining predictor of exosomal PD-L1 and lactate lower than - 0.249 was associated with a better ORR (82.1% vs. 30.0%, P < 0.001) and a longer median PFS (13.83 vs. 5.50 months, P < 0.001) compared to those with combining predictor ≥-0.249. The results also revealed that exosomal PD-L1 levels in peripheral blood plasma before the treatment were significantly correlated with the frequency of CD8⁺ T cells (P = 0.007), and in patients after receiving ICI plus XELOX, high exosomal PD-L1 level was associated with more PD-1⁺ Treg cells, high exosomal lactate level was associated with less CD8⁺ T cells and more Treg cells. Thus, the levels of PD-L1 and lactate in exosomes may affect the balance between Treg cells and CD8⁺T cells, leading to treatment resistance to ICI plus XELOX. Compared to PD-L1 expression level in tumor tissues, exosomal PD-L1 and lactate levels could more accurately predict clinical outcomes of HER2-negative patients with metastatic esophagogastric signet ring cell carcinoma receiving first-line PD-1 blockade plus chemotherapy.