Intratumoral plasma cells predict patient prognosis and responsiveness to neoadjuvant immunotherapy in advanced gastric cancer

Limited biomarker availability hinders the accurate prognostication of individual responses to immunotherapy in gastric cancer (GC). Mature tertiary lymphoid structures (mTLS) substantially affect immunotherapeutic efficacy in patients. However, the inherent limitations of tissue size in gastroscopic biopsies necessitate the development of a new mTLS marker-based classification strategy. An integrated analysis of multimodal data, including GC tissues collected from seven independent medical centers, single-cell transcriptomes, spatial transcriptomics, and transcriptome sequencing, revealed mTLS as a key site for somatic hypermutation and clonal selection in the infiltrating plasma cells of GC. An MZB1 positive score (MPS) was established based on the different degree of plasma cell infiltration between mTLS-positive (mTLS-Po) and mTLS-negative (mTLS-Ne) tumors characterizing MPS^High and MPS^Low statuses, respectively. MPS^High status and combined positive score ≥ 5 indicated a favorable outcome for anti-PD-1 therapy. Conclusively, MPS offers a valuable quantitative approach for improving clinical outcomes and guiding treatment decisions in GC.