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Li, Keyu; Tandurella, Joseph A.; Gai, Jessica; Zhu, Qingfeng; Lim, Su Jin; Thomas, Dwayne L.; Xia, Tao; Mo, Guanglan; Mitchell, Jacob T.; Montagne, Janelle; Lyman, Melissa; Danilova, Ludmila V.; Zimmerman, Jacquelyn W.; Kinny-Köster, Benedict; Zhang, Tengyi; Chen, Linda; Blair, Alex B.; Heumann, Thatcher; Parkinson, Rose; Durham, Jennifer N.; Narang, Amol K.; Anders, Robert A.; Wolfgang, Christopher L.; Laheru, Daniel A.; He, Jin; Osipov, Arsen; Thompson, Elizabeth D.; Wang, Hao; Fertig, Elana J.; Jaffee, Elizabeth M.; Zheng, Lei
Cancer cell, 11/2022, Volume: 40, Issue: 11Journal Article
Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy necessitates optimization and maintenance of activated effector T cells (Teff). We prospectively collected and applied multi-omic analyses to paired pre- and post-treatment PDAC specimens collected in a platform neoadjuvant study of granulocyte-macrophage colony-stimulating factor-secreting allogeneic PDAC vaccine (GVAX) vaccine ± nivolumab (anti-programmed cell death protein 1 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 was required for optimal T cell activation. These findings provide insights into PD-1-regulated immune pathways in PDAC that should inform more effective therapeutic combinations that include TAN regulators and T cell activators. Display omitted •Prospectively collected PDAC specimens from a neoadjuvant platform clinical trial•Identified sensitivity and resistance mechanisms to anti-PD-1 therapy in PDAC•Informed studies of additional immune-modulating agents in the ongoing platform trial•Generated hypotheses of reprogramed TME signals for combination immunotherapy strategies Li et al. perform multi-omic analyses on pre- and post-treatment specimens from a pancreatic cancer neoadjuvant platform trial, and identify sensitivity and resistance mechanisms associated with anti-PD-1 combination therapy. Results associate tumor-associated neutrophils with poor outcomes but CD137+CD8+ T cells with better outcomes, suggesting treatment strategies for future interventions.
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