title: Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma.
abstract: B-cell responses are emerging as critical regulators of cancer progression. In this study, we investigated the role of B lymphocytes in the microenvironment of human pancreatic ductal adenocarcinoma (PDAC), in a retrospective consecutive series of 104 PDAC patients and in PDAC preclinical models. Immunohistochemical analysis revealed that B cells occupy two histologically distinct compartments in human PDAC, either scatteringly infiltrating (CD20-TILs), or organized in tertiary lymphoid tissue (CD20-TLT). Only when retained within TLT, high density of B cells predicted longer survival (median survival 16.9 mo CD20-TLThivs. 10.7 mo CD20-TLTlo;p= 0.0085). Presence of B cells within TLT associated to a germinal center (GC) immune signature, correlated with CD8-TIL infiltration, and empowered their favorable prognostic value. Immunotherapeutic vaccination of spontaneously developing PDAC (KrasG12D-Pdx1-Cre) mice with α-enolase (ENO1) induced formation of TLT with active GCs and correlated with increased recruitment of T lymphocytes, suggesting induction of TLT as a strategy to favor mobilization of immune cells in PDAC. In contrast, in an implanted tumor model devoid of TLT, depletion of B cells with an anti-CD20 antibody reinstated an antitumor immune response. Our results highlight B cells as an essential element of the microenvironment of PDAC and identify their spatial organization as a key regulator of their antitumor function. A mindfully evaluation of B cells in human PDAC could represent a powerful prognostic tool to identify patients with distinct clinical behaviors and responses to immunotherapeutic strategies.
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Giovanni Francesco
authors.initials: GF
authors.lastname: Castino
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Nina
authors.initials: N
authors.lastname: Cortese
authors.affiliation: Section of Pancreatic Surgery, Department of Surgery, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Capretti
authors.affiliation: Operational Unit of Milano; Institute of Genetics and Biomedical Research, National Research Council and Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Serio
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Caro
authors.affiliation: Molecular Biology Section, Clinical Investigation Laboratory, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Mineri
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Magrini
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grizzi
authors.affiliation: Center for Experimental Research and Medical Studies, Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Torino , Torino, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cappello
authors.affiliation: Center for Experimental Research and Medical Studies, Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Torino , Torino, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
authors.affiliation: Department of Pathology, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Spaggiari
authors.affiliation: Department of Pathology, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Roncalli
authors.affiliation: Section of Pancreatic Surgery, Department of Surgery, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ridolfi
authors.affiliation: Section of Pancreatic Surgery, Department of Surgery, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gavazzi
authors.affiliation: Section of Pancreatic Surgery, Department of Surgery, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zerbi
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center , Rozzano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Allavena
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milano, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Marchesi
keywords: B cells; biomarkers; immunotherapy; pancreatic adenocarcinoma (PDAC); tertiary lymphoid tissue