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

Abstract

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. We delineate the mechanisms underlying the response and resistance, and elucidate the immune features that enhance neoadjuvant PD-L1 blockade efficacy in ESCC. 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. 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. Overall, our findings unravel the coordinated cellular programmes associated with treatment response, providing insights for prioritising individualised immunotherapy strategies in ESCC. ChiCTR2400083452.