Spatial Positioning and Matrix Programs of Cancer-Associated Fibroblasts Promote T-cell Exclusion in Human Lung...

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Cancer-associated fibroblasts (CAFs) are known to influence the tumor microenvironment and immune cell infiltration.
• T-cell exclusion from solid tumors is a significant barrier to effective cancer immunotherapy.

Purpose of the Study:

• To unbiasedly identify and characterize CAF populations responsible for T-cell exclusion in lung tumors.
• To understand the molecular and structural mechanisms by which CAFs mediate T-cell marginalization.

Main Methods:

• Single-cell RNA sequencing and multiplex imaging were employed on a large cohort of lung tumors.
• Identification and spatial characterization of distinct CAF subpopulations based on molecular markers and tissue organization.

Main Results:

• Four main CAF populations were identified, with two specifically linked to T-cell exclusion: MYH11+αSMA+ CAF (early-stage) and FAP+αSMA+ CAF (advanced-stage).
• These exclusionary CAF populations deposit dense, aligned fibers, creating a distinct tissue architecture compared to T cell-permissive CAFs.
• MYH11+αSMA+ CAF secrete collagen IV, while FAP+αSMA+ CAF secrete collagen XI/XII, contributing to differential matrix organization.

Conclusions:

• Specific CAF subpopulations orchestrate T-cell exclusion in lung tumors through unique molecular programs and structural modifications.
• Targeting these T cell-excluding CAF populations presents a potential strategy to enhance immunotherapy efficacy in patients with T cell-excluded tumors.