Multi-omics analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 antibody

Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy necessitates optimization and maintenance of activated effector T cells (Teffs). We prospectively collected and applied multi-omics analysis to paired, pre- and post-treatment PDAC specimens collected in a platform neoadjuvant study of GVAX vaccine +/- nivolumab (anti-PD-1) to uncover sensitivity and resistance mechanisms. We show that GVAX-induced tertiary lymphoid aggregates become immune-regulatory sites in response to GVAX+nivolumab. Higher densities of tumor-associated neutrophils (TANs) following GVAX+nivolumab portend poorer overall survival (OS). Increased T cells expressing CD137 associated with cytotoxic Teff signatures and correlated with increased OS. Bulk and single-cell RNA-sequencing found that nivolumab alters CD4+ T cell chemotaxis signaling in association with CD11b+ neutrophil degranulation, and CD8+ T cell expression of CD137 required for optimal T cell activation. These findings provide new insights into PD-1-regulated immune pathways in PDAC that should inform more effective therapeutic combinations that include TAN regulators and T cell activators. Examination of patients participating in the studied clinical trial (NCT02451982). Read counts used in Cancer Cell available as GSE197613_NewGeneCounts.txt.gz and used for the normalization in JEM as GSE197613_JEM_counts_combined_TIIC-RNA-seq.txt.gz and GSE197613_JEM_gene_logtpm_filtered_TMM_qn_normalized_nivo_select_TIIC-RNA-seq.txt.gz. **RAW data will be submitted to dbGAP**