Interleukin Family-Based Signature Relates to Cancer-Associated Fibroblasts Spatial Distribution and Immune Therapy Response in Pancreatic Carcinoma.

Background: Cancer-associated fibroblasts (CAFs) and interleukins (ILs) family play crucial roles in pancreatic carcinoma (PC) immune response. However, the correlation between the IL family, CAFs infiltration, and PC prognosis remains uninvestigated.

Methods: An IL family expression pattern for prognosis was constructed using a stepwise Cox proportional hazards regression model using TCGA data. Clinical data and validations from seven independent public cohort datasets were conducted to confirm the performance of the model. CAFs infiltrating abundance and spatial distribution in PC, and their correlation with patient prognosis were detected. Correlation between IL expression pattern, CAF infiltration, and immunotherapy response was evaluated using clinical tissue samples.

Results: This study constructed the first IL family expression pattern to predict CAFs infiltration and prognosis in PC. The model was validated using clinical data and a meta-analysis of seven public PC datasets (HR= 1.27). IL high-risk patients had shorter survival, advanced tumors and lymph node metastasis compared to low-risk patients. Patients with unfavorable immunotherapy response had significantly higher IL risk scores (P=0.015). The IL expression pattern distinguished CAFs infiltration characteristics in PC, showing greater infiltration of CAFs, antigen-presenting CAFs (apCAFs) and inflammatory CAFs in the high-risk group. IL high-risk group also exhibited increased apCAF/tumor cell and apCAF/Tregs engagement, resulting in suppressed immune responses, crippled T-cell function and B-cell function, and elevated levels of biomarkers associated with poor immune response.

Conclusion: This study constructed the first IL expression pattern related to CAFs infiltration, immunotherapy response, and prognosis in PC patients. This might promote precise immunotherapy and facilitate treatment options for PC.