B lymphocytes contribute to stromal reaction in pancreatic ductal adenocarcinoma

Claudia Minici, Elena Rigamonti, Marco Lanzillotta, Antonella Monno, Lucrezia Rovati, Takashi Maehara, Naoki Kaneko, Vikram Deshpande, Maria Pia Protti, Lucia De Monte, Cristina Scielzo, Stefano Crippa, Paolo Giorgio Arcidiacono, Erica Dugnani, Lorenzo Piemonti, Massimo Falconi, Shiv Pillai, Angelo A. Manfredi, Emanuel Della-Torre

Research output: Contribution to journalArticle

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent stromal reaction that has been variably implicated in both tumor growth and tumor suppression. B-lymphocytes have been recently implicated in PDAC progression but their contribution to the characteristic stromal desmoplasia has never been assessed before. In the present work, we aimed to verify whether B-lymphocytes contribute to stromal cell activation in PDAC. CD19+ B-lymphocytes purified from peripheral blood of patients with PDAC were cultivated in the presence of human pancreatic fibroblasts and cancer-associated fibroblasts. Released pro-fibrotic soluble factors and collagen production were assessed by ELISA and Luminex assays. Quantitative RT-PCR was used to assess fibroblast activation in the presence of B cells. The expression of selected pro-fibrotic and inflammatory molecules was confirmed on PDAC tissue sections by multi-color immunofluorescence studies. We herein demonstrate that B-cells from PDAC patients (i) produce the pro-fibrotic molecule PDGF-B and stimulate collagen production by fibroblasts; (ii) express enzymes implicated in extracellular matrix remodeling including LOXL2; and (iii) produce the chemotactic factors CCL-4, CCL-5, and CCL-11. In addition we demonstrate that circulating plasmablasts are expanded in the peripheral blood of patients with PDAC, stimulate collagen production by fibroblasts, and infiltrate pancreatic lesions. Our results indicate that PDAC is characterized by perturbations of the B-cell compartment with expansion of B-lymphocyte subsets that directly contribute to the stromal reaction observed at disease site. These findings provide an additional rationale for modulating B-cell activity in patients with pancreatic cancer.

Original languageEnglish
Article number1794359
JournalOncoImmunology
Volume9
Issue number1
DOIs
Publication statusPublished - Jan 1 2020

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Oncology

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    Minici, C., Rigamonti, E., Lanzillotta, M., Monno, A., Rovati, L., Maehara, T., Kaneko, N., Deshpande, V., Protti, M. P., De Monte, L., Scielzo, C., Crippa, S., Arcidiacono, P. G., Dugnani, E., Piemonti, L., Falconi, M., Pillai, S., Manfredi, A. A., & Della-Torre, E. (2020). B lymphocytes contribute to stromal reaction in pancreatic ductal adenocarcinoma. OncoImmunology, 9(1), [1794359]. https://doi.org/10.1080/2162402X.2020.1794359