Abstract 228P
Background
The extracellular matrix (ECM) is pivotal in tumor progression. Increased ECM stiffness is known to impact the immune response and foster tumor progression. However, the specific effects on lung adenocarcinoma (LUAD) remain unclear.
Methods
We extracted decellularized lung and tumor ECM from LUAD patients at T1 (3 and 5 cm) stages. Matrix viscoelasticity was assessed via rheological analysis. Micromorphology was examined using transmission electron microscopy and scanning electron microscopy. Differences in matrix components were evaluated through proteomic analysis. In vitro ECM reconstruction was achieved by crosslinking type VII collagen to mimic the tumor microenvironment. Macrophages and lymphocytes were co-cultured with the in vitro ECM. The expression and prognostic significance of type VII collagen were further validated in an external cohort from a public database.
Results
Matrix viscoelasticity significantly increased in advanced stages. The fibril collagen in the ECM of advanced stages (T2 and T3) was significantly thicker and more encasing of tumors compared to the T1 stage. Proteomic analysis of LUAD ECM revealed that COL7A1 expression was positively correlated with enhanced matrix viscoelasticity. Immunofluorescence showed that advanced tumor ECM exhibited increased expression of COL7A1, which was positively correlated with the infiltration levels of CD4+ T cell, and negatively correlated with the infiltration levels of CD8+ T cells in LUAD. In vitro co-culture of type VII collagen with macrophages and lymphocytes indicated that the antiinflammatory type was stimulated with up-regulation of CD206+ in macrophages, CD4+ and PD-1 expression in lymphocytes. GEPIA database analysis indicates that high expression of COL7A1 is associated with poorer overall survival and progression-free interval in LUAD patients. Additionally, COL7A1 expression was positively correlated with the infiltration of CD4 + T cells, along with increased expressions of PD-1 and PD-L1.
Conclusions
COL7A1 expression correlates with enhanced matrix viscoelasticity, immunosuppressive state and poorer clinical outcomes of advanced LUAD.
Legal entity responsible for the study
The authors.
Funding
Beijing Natural Science Foundation (7232134); CAMS Initiative for Innovative Medicine (2021-1-I2M-012); National High-Level Hospital Clinical Research Funding (2022-PUMCH-C-043); Fundamental Research Funds for the Central Universities (No. 3332024205).
Disclosure
All authors have declared no conflicts of interest.