Plasminogen Activator Inhibitor-1 Mediates Tolerance to Anti-PD-1 Immunotherapy in Non-Small Cell Lung Cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immune checkpoint inhibitors (ICIs) have improved outcomes for non-small-cell lung cancer (NSCLC) patients, yet cure rates remain limited due to the survival of tolerant persister cancer cells.
• Plasminogen activator inhibitor-1 (PAI-1) has been previously implicated in acquired resistance to targeted therapies in NSCLC.

Purpose of the Study:

• To investigate the role of PAI-1 in the development of tolerance to ICI therapy in NSCLC.
• To evaluate PAI-1 as a potential therapeutic target to overcome ICI resistance.

Main Methods:

• Establishment of an anti-programmed death-1 (aPD-1) antibody-tolerant persister cell (aPD-1-TP) model in mice using Lewis lung carcinoma or KLN205 cells.
• Analysis of gene expression, immunohistochemistry for tumor microenvironment components (TAMs, PD-L1, angiogenesis, TILs), and tumor growth inhibition.
• Combination treatment with aPD-1 antibody and the PAI-1 inhibitor TM5614.

Main Results:

• aPD-1-TPs exhibited higher PAI-1 and mesenchymal gene expression compared to control cells.
• Tolerant tumors showed increased tumor-associated macrophages (TAMs), programmed death-ligand 1 (PD-L1) expression, and angiogenesis, with fewer tumor-infiltrating lymphocytes (TILs).
• Combination therapy with aPD-1 antibody and TM5614 reduced mesenchymal markers, PD-L1, TAMs, and angiogenesis, while increasing TILs, leading to prolonged tumor growth inhibition.

Conclusions:

• PAI-1 contributes to the survival of ICI-tolerant persister cells in NSCLC, potentially through epithelial-mesenchymal transition and modulation of the tumor microenvironment.
• Combined ICI and PAI-1 inhibition represents a promising therapeutic strategy for overcoming ICI resistance in NSCLC.