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

• DOI: 10.1016/j.ccell.2022.10.001
• Publication Date: 2022-10-27T15:00:31Z
• Authors: Keyu Li; Joseph A. Tandurella; Jessica Gai; Qingfeng Zhu; Su Jin Lim; Dwayne L. Thomas; Tao Xia; Guanglan Mo; Jacob T. Mitchell; Janelle Montagne; Melissa Lyman; Ludmila V. Danilova; Jacquelyn W. Zimm...; Benedict Kinny-Kö...; Tengyi Zhang; Linda Chen; Alex B. Blair; Thatcher Heumann; Rose Parkinson; Jennifer N. Durham; Amol K. Narang; Robert A. Anders; Christopher L. Wo...; Daniel A. Laheru; Jin He; Arsen Osipov; Elizabeth D. Thom...; Hao Wang; Elana J. Fertig; Elizabeth M. Jaffee; Lei Zheng
• Keywords: Neoadjuvant Therapy

Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy necessitates optimization and maintenance of activated effector T cells (Teff). We prospectively collected applied multi-omic analyses to paired pre- post-treatment PDAC specimens in a platform neoadjuvant study granulocyte-macrophage colony-stimulating factor-secreting allogeneic vaccine (GVAX) ± nivolumab (anti-programmed cell death protein 1 [PD-1]) uncover sensitivity resistance mechanisms. show that GVAX-induced tertiary lymphoid aggregates become immune-regulatory sites response GVAX + nivolumab. Higher densities tumor-associated neutrophils (TANs) following portend poorer overall survival (OS). Increased expressing CD137 associated with cytotoxic Teff signatures correlated increased OS. Bulk single-cell RNA sequencing found alters CD4+ chemotaxis signaling association CD11b+ neutrophil degranulation, CD8+ expression was required for optimal activation. These findings provide insights into PD-1-regulated immune pathways should inform more effective therapeutic combinations include TAN regulators activators.