Abstract
Thyroid transcription factor-1 (TTF-1) is a lineage-specific marker for lung adenocarcinoma (LUAD), whereas the relatively minor subset of TTF-1-negative LUADs shows a poor prognosis and a limited response to therapy. However, its relationship with the tumor immune microenvironment remains poorly defined. How TTF-1 expression affects the immune context in LUAD was investigated, focusing on tumor-associated macrophages (TAMs) and T-cell infiltration. Immunohistochemical (IHC) analysis of 226 LUAD specimens showed that TTF-1-negative tumors were associated with epidermal growth factor receptor wild-type status, advanced stage, and worse progression-free and cancer-specific survivals. Notably, PD-L1 (programmed death-ligand 1) and PD-L2 expression in TAMs, but not in cancer cells, was significantly reduced in TTF-1-negative tumors. Public single-cell RNA sequencing data confirmed downregulation of CD274 (PD-L1) in TAMs from tumors with low expression of TTF-1-related genes. In contrast, PDCD1LG2 (PD-L2) expression showed less consistent patterns. On IHC analysis, infiltration of CD8(+) and CD4(+) T cells was modestly lower in TTF-1-negative tumors, accompanied by decreased HLA class I and II expressions. Transcriptomic analysis of The Cancer Genome Atlas LUAD cohort further showed lower interferon gamma (IFN-γ) signaling and decreased T cell-inflamed gene signatures in the low TTF-1-negative tumors. These findings suggest that TTF-1-negative LUAD exhibits more immune-suppressive features, with a relatively reduced antitumor immune response characterized by decreased T-cell infiltration and INF-γ signaling, which are related to PD-L1 and PD-L2 expressions in TAMs.