Neoadjuvant Immunotherapy Promotes the Formation of Mature Tertiary Lymphoid Structures in a Remodeled Pancreatic Tumor Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly pro- expression matrix factorization methods for spatial trangressing cancer that responds poorly to immunotherapies. scriptomics, we characterized cellular states within and adjacent Intratumoral tertiary lymphoid structures (TLS) have been as- to TLS spanning distinct spatial niches and pathologic responses. sociated with rare long-term PDAC survivors, but the role of TLS Unsupervised learning identified TLS-specific spatial gene ex-in PDAC and their spatial relationships within the context of the pression signatures that are significantly associated with imbroader tumor microenvironment remain unknown. In this proved survival in patients with PDAC. We identified spatial study, we report the generation of a spatial multiomic atlas of features of pathologic immune responses, including intratumoral PDAC tumors and tumor-adjacent lymph nodes from patients TLS–associated B-cell maturation colocalizing with IgG dissemtreated with combination neoadjuvant immunotherapies. Using ination and extracellular matrix remodeling. Our findings offer machine learning–enabled hematoxylin and eosin image classi- insights into the cellular and molecular landscape of TLS in fication models, imaging mass cytometry, and unsupervised gene PDACs during immunotherapy treatment.