The impact of local tumor immune responses on prognosis in resected lung adenocarcinoma

Background: Tertiary lymphoid structures (TLS) have been identified in the tumor microenvironment and are increasingly recognized as playing a critical role in local antitumor immune responses. The recurrence-preventive effects observed with perioperative immune checkpoint inhibitors (ICIs) suggest that the immune status of patients undergoing lung cancer resection may significantly influence prognosis. This study analyzed the associations between prognosis and immune cell composition within TLS, including CD8⁺ T cells, CD4⁺ T cells, and B cells, as well as the areas of TLS and high endothelial venules (HEVs), which are essential for TLS formation and immune cell infiltration, in resected lung adenocarcinoma.

Methods: This study included 100 patients with lung adenocarcinoma who underwent surgical resection at our institution between January 2018 and January 2019. Representative tumor tissue sections from each case were subjected to multiplex immunofluorescence staining using antibodies against CD8, CD4, CD20, MECA-79, and cytokeratin. The numbers of immune cells within TLS, including CD8⁺ T cells, CD4⁺ T cells, and B cells, as well as the areas of TLS and HEVs, were quantified using a multiplex immunofluorescence and multispectral imaging system.

Results: Univariate analysis showed that TLS area, HEV area, CD4⁺ T cell count within TLS, pathological lepidic growth percentage, and pathological stage as significant prognostic factors. In multivariate analysis, TLS area and pathological stage remained independent prognostic factors. A strong positive correlation was observed between TLS area and HEV area, with larger TLS areas associated with larger HEV areas. In contrast, no significant correlations were detected between TLS area and the numbers of lymphocyte subsets within TLS (CD4⁺, CD20⁺, or CD8⁺ cells). No significant association was observed between TLS area and pathological lepidic growth percentage.

Conclusions: In patients with resected lung adenocarcinoma, TLS area is an independent favorable prognostic factor, and TLS formation is associated with improved clinical outcomes. A significant correlation exists between TLS area and HEV area.