Sidiropoulos et al. report state-of-the-art spatial genomics and proteomic profiling of PDAC tumors and tumor-adjacent lymph nodes from patients treated with GVAX and anti-PD-1 alone or in combination with a 41BB agonist in the neoadjuvant setting. Spatial transcriptomics identified TLS-specific spatial gene expression signatures associated with improved survival in TCGA PDAC samples. TLS-adjacent stroma of pathologic responders showed ECM remodeling with decreased desmoplasia. Neoadjuvant immunotherapy induced TLS formation in diverse spatial niches with mature B cell aggregates that disseminate IgG antibodies.
Contributed by Shishir Pant
ABSTRACT: Pancreatic 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. Herein, we report the generation of a spatial multi-omics 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 across distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that significantly associated with improved survival in PDAC patients. 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.
Author Info: (1) Johns Hopkins Medicine, Baltimore, United States. (2) Johns Hopkins Medicine, Baltimore, MD, United States. (3) Johns Hopkins Medicine, United States. (4) Johns Hopkins Univers
Author Info: (1) Johns Hopkins Medicine, Baltimore, United States. (2) Johns Hopkins Medicine, Baltimore, MD, United States. (3) Johns Hopkins Medicine, United States. (4) Johns Hopkins University, United States. (5) Johns Hopkins Medicine, United States. (6) Johns Hopkins Medicine, Baltimore, Maryland, United States. (7) Johns Hopkins University, United States. (8) University of Maryland Medical Center, Baltimore, MD, United States. (9) Johns Hopkins University, Baltimore, MD, United States. (10) Johns Hopkins Medicine, Baltimore, MD, United States. (11) Johns Hopkins University, Baltimore, MD, United States. (12) Johns Hopkins University, United States. (13) Johns Hopkins University, United States. (14) Johns Hopkins University, Baltimore, Maryland, United States. (15) Johns Hopkins Medicine, Baltimore, Maryland, United States. (16) Johns Hopkins Medicine, Baltimore, United States. (17) Johns Hopkins University, Baltimore, United States. (18) Johns Hopkins Medicine, Baltimore, MD, United States. (19) Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States. (20) Johns Hopkins Medicine, Baltimore, MARYLAND, United States. (21) Johns Hopkins University, Baltimore, MD, United States. (22) Johns Hopkins University, Baltimore, MD, United States. (23) Johns Hopkins University, Baltimore, MD, United States. (24) Johns Hopkins University, Baltimore, MD, United States. (25) Johns Hopkins Medicine, Baltimore, Maryland, United States. (26) Johns Hopkins University, Baltimore, MD, United States. (27) Johns Hopkins Medicine, Baltimore, United States. (28) University of Maryland, Baltimore, Baltimore, Maryland, United States. (29) Johns Hopkins University, Baltimore, MD, United States.
