Neoadjuvant Immunochemotherapy Increases the Abundance of Tertiary Lymphoid Structures and Lymphocyte Subpopulations Is Associated With Prognosis of Esophageal Squamous Cell Carcinoma

Neoadjuvant immunochemotherapy (NIC) has emerged as a promising strategy for esophageal squamous cell carcinoma (ESCC). However, its impact on tertiary lymphoid structures (TLSs) and the immune microenvironment remains to be fully elucidated. We retrospectively analyzed 50 ESCC patients treated with NIC (n = 25) or chemotherapy alone (n = 25) between 2021 and 2023. TLSs and lymphocyte subpopulations in paired tumor tissues were assessed via multiplex immunofluorescence. Disease-free survival (DFS) was evaluated using Cox regression, and correlations with peripheral blood lymphocytes were analyzed. NIC significantly increased the abundance and maturity of TLSs compared to chemotherapy alone. Specifically, NIC-induced TLSs were enriched with CD3 + CD8 + PD-1+ T cells and CD103 + CXCL13+ dendritic cells (DCs). Clinically, the NIC group demonstrated a significantly prolonged median DFS compared to the chemotherapy group (17.4 vs. 13.5 months, p = 0.009). High abundance of mature TLSs was an independent predictor of improved DFS (HR = 0.45). Furthermore, elevated proportions of CD3 + CD8 + PD-1+ T cells and CD103 + CXCL13+ DCs within TLSs were strongly associated with longer survival. These local TLS alterations also correlated with specific changes in peripheral blood lymphocyte subsets. Our preliminary data suggest that NIC promotes TLS maturation and is associated with enrichment of specific immune subsets within TLSs. CD3 + CD8 + PD-1+ T cells and CD103 + CXCL13+ DCs may serve as exploratory biomarkers associated with prognosis and immunotherapy response.