Search

Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy requires therapeutic combinations that induce quality T cells. Tumor microenvironment (TME) analysis following therapeutic interventions can identify response mechanisms, informing design of effective combinations. We provide a reference single-cell dataset from tumor-infiltrating leukocytes (TILs) from a human neoadjuvant clinical trial comparing the granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic PDAC vaccine GVAX alone, in combination with anti-PD1 or with both anti-PD1 and CD137 agonist. Treatment with GVAX and anti-PD-1 led to increased CD8 + T cell activation and expression of cytoskeletal and extracellular matrix (ECM)-interacting components. Addition of CD137 agonist increased abundance of clonally expanded CD8 + T cells and increased immunosuppressive TREM2 signaling in tumor associated macrophages (TAMs), identified by comparison of ligand-receptor networks, corresponding to changes in metabolism and ECM interactions. These findings associate therapy with GVAX, anti-PD1, and CD137 agonist with enhanced CD8 + T cell function while inducing alternative immunosuppressive pathways in patients with PDAC., Competing Interests: L.Z. receives grant support from Bristol Myers Squibb, Merck, Astrazeneca, iTeos, Amgen, NovaRock, Inxmed, and Halozyme. L.Z. is a paid consultant/advisory Board Member at Biosion, Alphamab, NovaRock, Ambrx, Akrevia/Xilio, QED, Natera, Novagenesis, Snow Lake Capitals, BioArdis, Amberstone Biosciences, Tempus, Pfizer, Tavotek Lab, Clinical Trial Options, LLC, and Mingruizhiyao. L.Z. holds shares at Alphamab, Amberstone, and Mingruizhiyao. E.M.J. reports other support from Abmeta and Adventris, personal fees from Achilles, Dragonfly, Mestag, The Medical Home Group, and Surgtx, other support from Parker Institute, grants and other support from the Lustgarten Foundation, Genentech, BMS, and Break Through Cancer outside the submitted work. E.S.C. receives grant support from Affimed GmbH, NextCure, Pfizer, Haystack Oncology, Regeneron and is a consultant for Seres Therapeutics and SIRTex. R.A.A. receives grant support from Bristol-Meyer Squibb, RAPT Therapeutics. R.A.A. is a paid consultant for Bristol-Meyer Squibb, Merck, and Astrazeneca. S.Y. reports grants from NIH and Maryland Cigarette Restitution Fund during the conduct of the study, grants and personal fees from Cepheid, other support from Digital Harmonic, and grants from Janssen and Bristol Myers Squibb outside the submitted work. J.H.E. was previously a consultant and holds equity in Unity Biotechnology, Aegeria Soft Tissue and is an advisor for Tessera Therapeutics, HapInScience, Regenity, and Font Bio. W.J.H. has patent royalties from Rodeo/Amgen, grants from Sanofi and NeoTX, and speaking/travel honoraria from Exelixis and Standard BioTools. J.W.Z. reports grant funding from Genentech.

This study introduces a new imaging, spatial transcriptomics (ST), and single-cell RNA-sequencing integration pipeline to characterize neoplastic cell state transitions during tumorigenesis. We applied a semi-supervised analysis pipeline to examine premalignant pancreatic intraepithelial neoplasias (PanINs) that can develop into pancreatic ductal adenocarcinoma (PDAC). Their strict diagnosis on formalin-fixed and paraffin-embedded (FFPE) samples limited the single-cell characterization of human PanINs within their microenvironment. We leverage whole transcriptome FFPE ST to enable the study of a rare cohort of matched low-grade (LG) and high-grade (HG) PanIN lesions to track progression and map cellular phenotypes relative to single-cell PDAC datasets. We demonstrate that cancer-associated fibroblasts (CAFs), including antigen-presenting CAFs, are located close to PanINs. We further observed a transition from CAF-related inflammatory signaling to cellular proliferation during PanIN progression. We validate these findings with single-cell high-dimensional imaging proteomics and transcriptomics technologies. Altogether, our semi-supervised learning framework for spatial multi-omics has broad applicability across cancer types to decipher the spatiotemporal dynamics of carcinogenesis., Competing Interests: Declaration of interests E.M.J. reports other support from Abmeta; personal fees from Genocea; personal fees from Achilles; personal fees from DragonFly; personal fees from Candel Therapeutics; other support from the Parker Institute; grants and other support from Lustgarten; personal fees from Carta; grants and other support from Genentech; grants and other support from AstraZeneca; personal fees from NextCure; and grants and other support from Break Through Cancer outside of the submitted work. E.J.F. is on the Scientific Advisory Board of Viosera Therapeutics/Resistance Bio and is a consultant to Mestag Therapeutics. W.J.H. reports patent royalties from Rodeo/Amgen and speaking/travel honoraria from Exelixis and Standard BioTools., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of interests L.Z. receives grant support from Bristol-Meyer Squibb, Merck, AstraZeneca, iTeos, Amgen, NovaRock, Inxmed, Halozyme, and Abmeta. L.Z. is a paid consultant/Advisory Board member at Biosion, Alphamab, NovaRock, Ambrx, Akrevia/Xilio, QED, Natera, Novagenesis, Snow Lake Capitals, BioArdis, Tempus, Amberstone, Pfizer, Tavotek, and Mingruizhiyao. L.Z. holds shares at Alphamab, Amberstone, and Mingruizhiyao. E.J.F. is on the scientific advisory board of Resistance Bio and is a paid consultant for Merck and Mestag Therapeutics. E.J. receives grant support from Lustgarten Foundation, Bristol-Meyer Squibb, Genentech, and AstroZeneca; is a paid consultant for NextCure, Genocea, DragonFly, Stimit, CSTONE, Achilles, and Candel; is on the advisory board of Parker Institute and Break Through Cancer; is a founder of Abmeta Biotech; and is the Chief Medical Advisor for the Lustgarten Foundation., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)