Cancer-Associated Fibroblasts Promote Immunosuppression by Inducing ROS-Generating Monocytic MDSCs in Lung Squamous...

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Cancer-associated fibroblasts (CAFs) are key components of the tumor stroma.
• CAFs promote tumor growth and chemotherapy resistance.
• CAF's role in immune suppression within the lung squamous cell carcinoma (LSCC) tumor microenvironment (TME) is understudied.

Purpose of the Study:

• To investigate the mechanisms by which CAFs contribute to immune suppression in LSCC.
• To explore the interplay between CAFs and monocytic myeloid cells in the LSCC TME.

Main Methods:

• Analysis of The Cancer Genome Atlas (TCGA) data and imaging mass cytometry for CAF-monocyte correlation and spatial interaction.
• Chemotaxis assays to assess monocyte recruitment by CAFs.
• Three-dimensional culture systems to evaluate CAF-induced monocyte polarization.
• Inhibition assays targeting CCR2, IDO1, NOX2, and NOX4 to assess effects on T-cell proliferation and ROS generation.

Main Results:

• A positive correlation and spatial interaction between CAFs and monocytic myeloid cells in LSCC TME were identified.
• LSCC CAFs recruit CCR2+ monocytes via CCL2, a process reversible by CCR2 inhibition.
• CAFs induce monocytes to differentiate into myeloid-derived suppressor cells (MDSCs) that suppress CD8+ T-cell proliferation and IFNγ production.
• Inhibition of IDO1 and NADPH oxidases (NOX2, NOX4) restored CD8+ T-cell proliferation by reducing ROS in MDSCs.

Conclusions:

• CAFs play a critical role in recruiting and differentiating monocytes into immunosuppressive MDSCs in LSCC.
• Targeting the CCR2 pathway and ROS production presents a potential therapeutic strategy to overcome CAF-mediated immune suppression in LSCC.