Background Gastric or gastroesophageal junction (G/GEJ) cancers is one of the most common lethal malignancies in the world. Near half of the G/GEJ cancers are locally advanced at diagnosis and with poor prognosis. Several clinical trials including which conducted in our center demonstrated that perioperative anti-PD-1 therapy in combination with concurrent chemoradiotherapy for locally advanced G/GEJ cancers could raise the pCR rate over 30%. However, the biomarkers for patients with pCR are nor clear.

Methods 34 patients with locally advanced G/GEJ cancer received anti-PD-1 therapy (Sintilimab) in combination with concurrent chemoradiotherapy in our center. Baseline tumor biopsies and post-treatment surgical tissues were collected for multiplex immunofluorescence (mIF), next-generation sequencing (NGS) and mass cytometry (CyTOF). The overall survival (OS) was measured from the date of surgery to the date of death or the last follow-up visit.

Results Our results met the pre-specified primary endpoint, with a pCR rate of 38.2% and median DFS of 17.0 months. Tumor mutation burden (TMB) analyzed by NGS was significantly higher in the pCR group than those not achieving pCR (non-pCR). Deletion of cytoband 7q35, where TPK1 locates, was significantly enriched in pCR groups while deletion of 11q14.3, which TRIM family sitting, was significantly enriched in non-pCR groups. Biomarker analysis by mIF showed patients with positive PD-L1 expression showed a numerically higher pCR rate. And, higher levels of infiltrating CD3⁺ T cells, CD4⁺ T cells, and CD56⁺natural killers (NKs) were found in patients achieving pCR. RNA sequencing data showed that CD4⁺ Th1 cell and plasmacytoid dendritic cell were significant enriched in pCR patients. Moreover, the proportion of CD127⁺CD27⁺HLA-DR^-CD38^-CD4 TCM defined by CyTOF was significantly lower in pCR patients. As continuous variable, only CD8⁺ T cell correlated with OS.

Conclusions It is consistent with the acknowledged prognostic biomarker of immunotherapy that positive PD-L1 expression, higher T cell infiltration and TMB could be predictive biomarkers of perioperative anti-PD-1 therapy in combination with cCRT for locally advanced G/GEJ. Furthermore, we found plasmacytoid dendritic cell, a new TCM subtype defined with CD127+CD27+HLA-DR-CD38- and deletion of cytoband 7q35 or 11q14.3 could be novel biomarkers.

Trial Registration CliniclaTrials ID: NCT05687357.

Ethics Approval This study followed the Declaration of Helsinki and Good Clinical Practice guidelines and was approved by the ethics committees of the Comprehensive Cancer Centre of Drum Tower Hospital (2019–093-02) and other participating centers. All patients provided written informed consent before any procedure.