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 months CD20-TLThi versus 10.7 months CD20-TLTlo; P=0.0085). Presence of B cells within TLT associated to a germinal center immune signature, correlated with CD8-TIL infiltration, and empowered their favorable prognostic value. Immunotherapeutic vaccination of spontaneously developing PDAC (KrasG12D-Pdx1-Cre) mice with alpha-enolase (ENO1) induced formation of TLT with active germinal centers 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.

Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma / G.F. Castino, N. Cortese, G. Capretti, S. Serio, G. Di Caro, R. Mineri, E. Magrini, F. Grizzi, P. Cappello, F. Novelli, C. Ridolfi, F. Gavazzi, A. Zerbi, P. Allavena, F. Marchesi. - In: ONCOIMMUNOLOGY. - ISSN 2162-4011. - 5:4(2016 Apr 02). [10.1080/2162402X.2015.1085147]

Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma

G. Di Caro;F. Marchesi
Ultimo
2016

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 months CD20-TLThi versus 10.7 months CD20-TLTlo; P=0.0085). Presence of B cells within TLT associated to a germinal center immune signature, correlated with CD8-TIL infiltration, and empowered their favorable prognostic value. Immunotherapeutic vaccination of spontaneously developing PDAC (KrasG12D-Pdx1-Cre) mice with alpha-enolase (ENO1) induced formation of TLT with active germinal centers 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.
B cells, pancreatic adenocarcinoma (PDAC), tertiary lymphoid tissue, biomarkers, immunotherapy
Settore MED/04 - Patologia Generale
2-apr-2016
2015
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/350788
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