The expression of PD-1 ligands in the immune microenvironment was altered in TTF-1-negative lung adenocarcinoma

Background: Immunotherapies targeting the programmed cell death-1 (PD-1) pathway have been adopted in lung adenocarcinoma (LUAD) treatment. Expression of programmed cell death-ligand 1 (PD-L1) and PD-L2 is observed in both cancer cells and tumor-associated macrophages (TAMs). PD-L1/L2 expression in TAMs is thought to be induced by inflammatory cytokines, such as interferon (IFN)-g. Thyroid transcription factor-1 (TTF-1) is a common diagnostic marker for LUAD, with TTF-1 negativity associated with poorer survival outcomes and reduced response to chemotherapy and immunotherapy. The present study investigated the correlation between TTF-1 expression and the immune microenvironment. Methods: TTF-1 status was evaluated using immunohistochemistry on paraffin-embedded samples from 226 patients with LUAD, examining the correlation of TTF-1 status with immune-related markers and immune cell infiltration. For further investigation, in silico RNA-seq analysis was performed. Results: TTF-1-negative cases showed worse progression-free survival and cancer-specific survival compared to TTF-1-positive cases. Additionally, TTF-1-negative cases exhibited lower PD-L1/L2 expression in TAMs, although no association was found between TTF-1 status and PD-L1/L2 expression in cancer cells. Consistent findings were observed through in silico analysis. The CD8 ⁺ T-cell density was generally lower in TTF-1-negative cases, a significant difference when cases with mutant epidermal growth factor receptor (EGFR) were excluded. Conclusions: These findings suggest that TTF-1-negative LUAD represents an immunologically “COLD” tumor, characterized by reduced infiltration of CD8 ⁺ T cells and a low IFN-g signature.