Coordinated cellular programmes distinguish responses to neoadjuvant PD-L1 blockade and potentiate combinatorial immunotherapy in ESCC.

BACKGROUND: Programmed death ligand 1 (PD-L1) blockade offers new therapeutic options for oesophageal squamous cell carcinoma (ESCC); however, the underlying mechanisms and associated biomarkers that determine treatment response remain unclear. OBJECTIVE: We delineate the mechanisms underlying the response and resistance, and elucidate the immune features that enhance neoadjuvant PD-L1 blockade efficacy in ESCC. DESIGN: Here, we characterise the cellular dynamics following neoadjuvant PD-L1 blockade via analysing the single-cell transcriptomes of 210 978 cells and spatial transcriptomes of 20 tissue sections. RESULTS: We identify coordinated cellular programmes centred on CXCL13+ CD8+ exhausted T cells, TNFRSF9+ CD4+ regulatory T cells, atypical memory B cells and APOE+ macrophages, which coordinate the responses to neoadjuvant PD-L1 blockade at baseline. In post-treatment non-responder ESCCs, the cellular programmes exhibit an immunosuppressive phenotype, leading to the failure of therapeutic benefits. Furthermore, we reveal that lymphocyte activation gene 3 serves as a potential target and can potentiate the response via perturbation of the coordinated cellular programmes. CONCLUSIONS: Overall, our findings unravel the coordinated cellular programmes associated with treatment response, providing insights for prioritising individualised immunotherapy strategies in ESCC. TRIAL REGISTRATION NUMBER: ChiCTR2400083452.