Neoadjuvant-induced Complement Upregulation in Tumor Microenvironment is Associated with Immunomodulation and Improved Survival in Pancreatic Ductal Adenocarcinoma: Insights from Spatially Resolved Transcriptomics

Recently neoadjuvant therapy (NAT) is being increasingly used in the treatment of pancreatic ductal adenocarcinoma (PDAC). However, how NAT differentially impacts the tumor and the tumor microenvironment (TME) is still poorly defined. Therefore, we compared the spatial transcriptomics profiles in tumor and the TME of PDACs resected from patients with versus without NAT. We found that NAT can significantly upregulate multiple key complement genes (C3, C1S, C1R, C4B and C7) in TME but not in tumor, making the complement pathway the most significantly modified pathways by NAT. In addition, the NAT-treated patients s with higher TME complement show significantly higher expression of gene signatures for immunomodulatory and neurotropic fibroblast, mast cells, CD4+ T cells and monocytes, significantly lower expression of immune exhaustion gene signature, and improved overall survival. Our results suggested that NAT may have immunostimulatory effect for PDAC through upregulating TME complement signaling. A total of 116 regions of interest (ROIs) with the most representative tumor morphology for each case were selected from the 36 patients in our cohort. Using immunofluorescence images, each ROI was further segmented into the tumor area (CK+, SMA-) and the TME area (CK-, SMA+). 223 (96.1%) of these 232 samples passed the quality control and were used for spatial transcriptomics analysis, including 42 TME samples and 43 tumor samples from the naïve group; and 72 TME samples and 66 tumor samples from the NAT group. *** FASTQ raw data files have been requested. ***