Integrative Multi-omics Reveals Myeloid Signatures of Neoadjuvant Chemotherapy Response in Pancreatic Ductal Adenocarcinoma (PDAC) 2254994

Abstract

Abstract Introduction Immune components, such as myeloid cells, including tumor-associated macrophages (TAMs), comprise a functionally diverse compartment of the PDAC tumor microenvironment capable of exerting both pro-tumorigenic and antitumor effects in response to microenvironmental cues. TAMs in solid tumors, including PDAC, are often considered to be immunosuppressive. However, due to their plasticity, they can aid anti-tumor immune responses. Among these TAM subsets, lipid-associated macrophages (LAMs) have recently emerged as a population enriched in lipid metabolism and phagocytic pathways. While some studies have used scRNA-seq and ATAC-Seq to identify distinct immune cell subsets in PDAC, none have focused on disparate chemotherapy responses in human PDAC. Thus, we performed multiomics sequencing to assess the transcriptomic and epigenomic landscape of PDAC tumors from patients who received neoadjuvant chemotherapy. Methods PDAC tissue samples from responders and non-responders were obtained from the WVU BIOTRAC Core upon surgical resection. Libraries for snMultiome + ATAC were prepared (10x Genomics) and sequenced by an Illumina sequencer. We performed single-cell annotation of major lineages, differential expression, and chromVAR TF-motif analysis. Results The cellular heterogeneity of the PDAC TME reveals distinct differences in the cell-type composition between the chemotherapy responders and non-responders. Responders showed an elevated lipid-associated macrophage (LAMs) population (38.4%) compared to non-responders (26.7%). Differential gene expression and enrichment analyses in responders’ myeloid cells highlighted phagocytosis and antigen presentation, suggesting functional reprogramming toward immune activation. Conclusion Neoadjuvant-treated PDAC tumors from responders exhibit a distinct myeloid landscape with enrichment of LAMs and immune-activating transcriptional/epigenetic programs, supporting a model in which immunometabolic reprogramming of myeloid cells contributes to therapeutic efficacy. Funding Source National Institute of General Medical Sciences, American Cancer Society, West Virginia Clinical and Translational Medicine, National Cancer Institute, and Hirshberg Foundation for Pancreatic Cancer Research Topic Categories Computational and Systems Immunology (COMP)