Decreased Tertiary Lymphoid Structures in Lung Adenocarcinomas with ALK Rearrangements

This study sought to characterize the tumor immune microenvironment (TIME) of lung adenocarcinomas with ALK rearrangements (ALK+ LUAD), which responds poorly to immune checkpoint inhibitors (ICIs) therapy.

Immune score evaluation and immunohistochemical (IHC) validation of B cells, cytotoxic, helper, regulatory T cells, dendritic cells, and tumor-associated macrophages were performed on the TCGA cohort and the whole tissue sections of our matched surgical samples, respectively, between ALK+ and ALK- LUAD. The formation and spatial organization of TLS, intra- and extra-TLS immune cell features, and tumor PD-L1 expression were analyzed independently.

Immune scores and TLS-signature gene levels were found to be lower in ALK+ TCGA LUAD. Quantitative IHC comparison confirmed the lower densities of TLS (0.10/mm² vs. 0.34/mm², p = 0.026) and intra-TLS immune cells (CD4+ helper T cells: 57.65/mm² vs. 274.82/mm², p = 0.026; CD8+ cytotoxic T cells: 22.46/mm² vs. 172.83/mm², p = 0.018; and CD20+ B cells: 36.08/mm² vs. 207.29/mm², p = 0.012) in ALK+ surgical samples. The TLS formation was negatively correlated with tumor progression in ALK+ tumors. The proportion of intra-TLS CD8+ cytotoxic T cells was the independent protective factors of node metastasis (HR: 0.599, 95% CI: 0.414-0.868, p = 0.007), and the density of intra-TLS CD20+ B cells was the independent protective factor of pStage (HR: 0.641, 95% CI: 0.446-0.922, p = 0.016). Tumors with intratumoral TLS showed significantly higher expression of PD-L1 (p = 0.029).

ALK+ LUAD harbored a cold TIME featured by decreased TLS formation, which closely correlated to tumor progression and might contribute to the poor efficiency of ICIs.