Predictive factors for neoadjuvant combined immunotherapy in gastric adenocarcinoma: Focusing on the primitive enterocyte phenotype and PVR.

BACKGROUND: Neoadjuvant combined immunotherapy has provided more treatment options for patients with gastric adenocarcinoma (GA). However, some GA patients, especially those with primitive enterocyte phenotype (GAPEP) show a poor response to immunotherapy, even with positive PD-L1 expression. METHOD: We enrolled multiple cohorts from our center and utilized public data to identify the predictive factors and explore the immunosuppressive features of GAPEP by multi-omics methods. RESULTS: Forty-seven patients with neoadjuvant combined immunotherapy were enrolled. After testing, we found PD-L1 combined positive score (CPS) ≥ 50 in biopsy tissues was significantly associated with major pathological response (MPR) (P = 0.04). RNA testing and immunohistochemical staining highlighted the cytotoxicity-associated markers (GZMA and PRF1) as the predictors to better response. Notably, GAPEP patients demonstrated resistance to therapy and exhibited worse survival outcomes. Our own and public bulk/single-cell transcriptomic analyses identified PVR as a predictor of treatment resistance and as an important immune suppressor, especially in GAPEP. Cell interaction analyses, multiple staining, and cell experiments verified the association between GAPEP and PVR. CONCLUSION: Cytotoxic markers, especially GZMA and PRF1, could predict the benefit of neoadjuvant combined immunotherapy in GA than PD-L1 CPS, while PVR is a negative predictor, particularly for GAPEP patients.