Predictive factors for neoadjuvant combined immunotherapy in gastric adenocarcinoma: Focusing on the primitive...

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.

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.

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.

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.