Spatial dynamics of CD39+CD8+ exhausted T cell reveal tertiary lymphoid structures-mediated response to PD-1 blockade in esophageal cancer

Abstract Despite the success of immune checkpoint blockade (ICB) therapy for esophageal squamous cell cancer, the key immune cell populations that affect ICB efficacy remain unclear. Here, imaging mass cytometry of tumor tissues from ICB-treated patients identifies a distinct cell population of CD39 + PD-1 + CD8 + T cells, specifically the TCF1 + subset, precursor exhausted T (CD39 + Tpex) cells, which positively correlate with ICB benefit. CD39 + Tpex cells are predominantly in the stroma, while differentiated CD39 + exhausted T cells are abundantly and proximally within the parenchyma. Notably, CD39 + Tpex cells are concentrated within and around tertiary lymphoid structure (TLS). Accordingly, tumors harboring TLSs have more of these cells in tumor areas than tumors lacking TLSs, suggesting Tpex cell recruitment from TLSs to tumors. In addition, circulating CD39 + Tpex cells are also increased in responders following ICB therapy. Our findings show that this unique subpopulation of CD39 + PD-1 + CD8 + T cells is crucial for ICB benefit, and suggest a key role in TLS-mediated immune responses against tumors.