PD-1 expression reprograms tumor-associated macrophages polarization and influences progression and clinical outcomes in lung adenocarcinoma

Abstract

Background

Programmed death-1 (PD-1) is critical in reprogramming tumor-associated macrophage (TAM) polarization and is associated with lung adenocarcinoma (LUAD) progression and prognosis. LUAD is the most common histological subtype of non-small cell lung cancer (NSCLC), but checkpoint blockade response rates remain below 20 %. Understanding PD-1/programmed death-ligand 1 (PD-L1)–TAM interactions in the tumor microenvironment (TME) is needed to improve outcomes.

Methods

Of 90 enrolled patients, 80 with pathologically confirmed LUAD (biopsy or post-surgery, January 2017–January 2019) were analyzed and divided into recurrence (n = 51) and non-recurrence (n = 29) groups. Receiver operating characteristic (ROC) analysis evaluated PD-1 for predicting recurrence; Kaplan-Meier curves analyzed PD-1 expression–disease-free survival (DFS) association. Flow cytometry assessed PD-1 effects on bone marrow-derived macrophage (BMDM) polarization. CCK-8 and Transwell assays assessed LA795 proliferation and migration.

Results

High PD-1 expression was associated with significantly shorter median DFS than low expression. PD-1 on BMDMs promoted M2 polarization, suppressed phagocytosis, and enhanced LA795 proliferation and migration, suggesting PD-1 on TAMs fosters an immunosuppressive TME and accelerates progression.

Conclusion

Elevated PD-1 expression correlates with poor prognosis in LUAD. In vitro, high macrophage PD-1 induced M2 polarization, inhibited phagocytosis, and indirectly promoted LUAD proliferation, migration, and epithelial–mesenchymal transition (EMT). These findings suggest PD-1 on TAMs may drive LUAD progression. However, these experiments were limited by a single murine tumor cell line, mouse BMDMs, and a conditioned medium system; moreover, missing treatment information means the clinical prognostic value of PD-1 requires further validation and cannot yet be directly applied to clinical risk assessment. Future in vivo animal experiments, multicellular models, and larger clinical cohorts with complete treatment information are needed to verify PD-1′s role in the TME and its clinical potential.