Non-spatial and spatial heterogeneity revealed a suppressive immune feature of Siglec-15 in lung adenocarcinomas

Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) has emerged as a novel immunotherapy candidate, which deserves a comprehensive investigation in lung adenocarcinoma (LUAD).

Multiplex fluorescence-based immunohistochemistry was conducted to assess Siglec-15 expression and tumor-infiltrating immune cells in LUAD from Tianjin cohort, with validation cohorts Xinchao 04 and 07.

This study revealed that Siglec-15 was positively correlated with CD8⁺ T cells and tumor-associated macrophages (TAMs) infiltration, but CD8⁺ T cells were mostly infiltrated in the stroma area, not in the tumor area. Spatially, fewer CD8⁺ T cells surrounded Siglec-15⁺ tumor cells in PD-L1^- cells, and more TAMs surrounded Siglec-15⁺ tumor cells in PD-L1^-/+ cells. Siglec-15⁺ TAMs infiltrated with more CD8⁺ T cells, and were closer to CD8⁺ T cells than Siglec-15^- TAMs and Siglec-15⁺ tumor cells. Siglec-15⁺ TAMs infiltrated with more Tregs and were closer to Tregs than Siglec-15⁺ tumor cells. Siglec-15⁺ tumor cells or TAMs reversed CD8⁺ T cells prognosis value, and enhanced the prognosis value of Tregs and TAMs. The immunotyping based on Siglec-15 and CD8A / CD8⁺ T cells revealed that patients with high CD8A and Siglec-15 expression exhibited immune activation. Patients with low CD8A expression / CD8⁺ T cells infiltration and Siglec-15 overexpression were related to the activation of immunosuppressive signature and metabolism-related pathway, and infiltrated with more TAMs.

We revealed the distinct characteristics between Siglec-15⁺ tumor cells and TAMs in relation to CD8⁺ T cells, and a unique relationship between Siglec-15 and immunosuppressive TIME in LUAD, which may provide potential value for anti-Siglec-15 therapy.