Neoadjuvant Immunotherapy Promotes the Formation of Mature Tertiary Lymphoid Structures in a Remodeled Pancreatic Tumor Microenvironment
Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. In this study, we report the generation of a spatial multiomic atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that are significantly associated with improved survival in patients with PDAC. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.
Authors
- Qingfeng Zhu (ORCID: https://orcid.org/0000-0001-7871-3359)
- Xuan Yuan (ORCID: https://orcid.org/0000-0002-7304-9927)
- Ashley Kiemen (ORCID: https://orcid.org/0000-0002-6281-2616)
- Guanglan Mo (ORCID: https://orcid.org/0009-0003-6519-3675)
- Robert A. Anders (ORCID: https://orcid.org/0000-0002-2363-9072)
- Elana J. Fertig (ORCID: https://orcid.org/0000-0003-3204-342X)
- Alexander A. Girgis (ORCID: https://orcid.org/0000-0002-4706-5480)
- Ludmila Danilova (ORCID: https://orcid.org/0000-0003-2813-3094)
- Janelle M. Montagne (ORCID: https://orcid.org/0000-0002-8113-1373)
- Won Jin Ho (ORCID: https://orcid.org/0000-0003-2644-5086)
- Elizabeth M. Jaffee (ORCID: https://orcid.org/0000-0003-3841-6549)
- Dimitrios N. Sidiropoulos (ORCID: https://orcid.org/0000-0001-5716-3917)
- Sarah M. Shin (ORCID: https://orcid.org/0000-0002-7658-5899)
- Victoria Jacobs (ORCID: https://orcid.org/0009-0008-6188-7502)
- Aleksandra Ogurtsova (ORCID: https://orcid.org/0009-0007-3064-1780)
- Genevieve Stein-O’Brien (ORCID: https://orcid.org/0000-0001-8681-9110)
- Dmitrijs Lvovs (ORCID: https://orcid.org/0009-0003-2152-6853)
- James M. Leatherman (ORCID: https://orcid.org/0000-0002-1721-2128)
- Mark Yarchoan (ORCID: https://orcid.org/0000-0003-4401-0748)
- Atul Deshpande (ORCID: https://orcid.org/0000-0001-5144-6924)
- Luciane T. Kagohara (ORCID: https://orcid.org/0000-0003-1706-0950)
- Ashani T. Weeraratna (ORCID: https://orcid.org/0000-0003-0448-6952)
- Daniel Bergman (ORCID: https://orcid.org/0000-0002-2166-6616)
- Elizabeth I. Harper (ORCID: https://orcid.org/0000-0002-3547-1692)
- Lucie Dequiedt (ORCID: https://orcid.org/0009-0006-1683-2161)
- Lei Zheng (ORCID: https://orcid.org/0000-0003-4163-2541)
- Susheel Perikala (ORCID: https://orcid.org/0009-0009-4558-6782)
- Meredith Wetzel (ORCID: https://orcid.org/0009-0005-6955-3521)
Institutions
- University of Maryland, Baltimore (US)
- University of Maryland Medical Center (US)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
- University of Baltimore (US)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1158/2326-6066.cir-25-0387
- Citations
- 5
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 4.03