Tertiary lymphoid structures (TLSs) were associated with survival in esophageal squamous cell carcinoma (ESCC) undergoing surgery alone (SA). However, their clinical relevance in neoadjuvant therapies remains less known. Here, we firstly investigated the presence, maturation and spatial distribution of TLSs in 359 ESCC patients receiving neoadjuvant chemotherapy (NCT), neoadjuvant immunotherapy (NCI), neoadjuvant chemoradiotherapy (NCRT) or SA. We found mature TLS (MTLS) was an independent prognostic factor in ESCC. NCI group had the lowest immature TLS cases. NCRT group had the lowest MTLSs. MTLSs mostly located in stromal and normal compartments; these MTLSs were positively correlated with neoadjuvant therapy outcomes. NCI group displayed the highest T cells within 150 mu m proximity of TLSs among the four groups. Most T cells were dispersed up to more than 150 mu m from TLSs, while B cells remained concentrated within TLSs. Innate lymphoid cells and follicular dendritic cells infiltrated and connected with survival differently in NCRT and NCI groups compared with SA group. The novel PD-L1 combined positive score, NCPS, was positively connected with MTLSs and neoadjuvant therapy efficacy. ScRNA-seq analysis revealed TLS+ + tumors had increased plasma cells, B cells, Th17, Tfh and Th1, and elevated exhausted CD8+ + T cells that highly expressed checkpoint molecules and granzymes. Conclusively, MTLSs favored treatment outcome in ESCC patients receiving multiple neoadjuvant therapies. The spatial distribution of MTLSs was associated with multiregional immune status modified by the neoadjuvant therapies.
[1]Tianjin Med Univ, Natl Clin Res Ctr Canc, Tianjins Clin Res Ctr Canc, Canc Inst & Hosp,Dept Radiat Oncol,Key Lab Canc Pr, Tianjin, Peoples R China.
[2]Tianjin Med Univ, Natl Clin Res Ctr Canc, Tianjins Clin Res Ctr Canc, Canc Inst & Hosp,Dept Immunol,Key Lab Canc Immunol, Tianjin, Peoples R China.
[3]Tianjin Med Univ, Natl Clin Res Ctr Canc, Key Lab Canc Prevent & Therapy, Canc Inst & Hosp,Dept Pathol,Tianjins Clin Res Ctr, Tianjin, Peoples R China.
[4]Tianjin Med Univ, Natl Clin Res Ctr Canc, Tianjins Clin Res Ctr Canc, Canc Inst & Hosp,Dept Endoscopy Diag & Therapy,Key, Tianjin, Peoples R China.
[5]Tianjin Med Univ, Natl Clin Res Ctr Canc, Tianjins Clin Res Ctr Canc, Canc Inst & Hosp,Key Lab Canc Prevent & Therapy,De, Tianjin, Peoples R China.
[6]Tianjin Med Univ, Natl Clin Res Ctr Canc, Tianjins Clin Res Ctr Canc, Canc Inst & Hosp,Dept Nutr Therapy,Key Lab Canc Pr, Tianjin, Peoples R China.
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