Yang Cheng,1,2,* Shuzhe Xiao,3,* Xiangzhao Li,4,* Biao Wang,5 Yi Lei,1 Penghui Sun,6 Li Ma,2 Yun Zhu1 

1Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology; Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, Guangdong, 510515, People’s Republic of China; 2Digestive Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 510623, People’s Republic of China; 3Department of Neonatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 4Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 5Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 6Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yun Zhu, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China, Email zyfreemail@126.com

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.

Keywords: pancreatic carcinoma, IL family, cancer-associated fibroblasts infiltration, immunotherapy response, prognosis