B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC. Our analysis revealed that TME contains diverse B cell clusters, including VISTA+ Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA+ Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-beta, IL-6, tumor necrosis factor (TNF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4+/CD8+ T lymphocytes in TME. The computational analysis of intercellular communications that links ligands to target genes, performed by NicheNet, predicted B-T interactions via VISTA-PSGL-1 axis. Colocalization analyses revealed that PSGL-1 T cells and VISTA+ B cells are adjacent in the TME. Notably, tumor infiltrating CD8+ T cells expressing PSGL-1 exhibited enhanced metabolism and cytotoxicity. In NSCLC patients, prediction analysis performed by PENCIL revealed the presence of an association between PSGL-1+CD8+ T cells and VISTA+ Bregs with lung recurrence. Our findings suggest a potential interaction between Bregs and T cells through the VISTA-PSGL-1 axis, that could influence NSCLC recurrence.

Metabolically activated and highly polyfunctional intratumoral VISTA+ regulatory B cells are associated with tumor recurrence in early-stage NSCLC / Lo Tartaro, Domenico; Aramini, Beatrice; Masciale, Valentina; Paschalidis, Nikolaos; Lofaro, Francesco Demetrio; Neroni, Anita; Borella, Rebecca; Santacroce, Elena; Ciobanu, Alin Liviu; Samarelli, Anna Valeria; Boraldi, Federica; Quaglino, Daniela; Dubini, Alessandra; Gaudio, Michele; Manzotti, Gloria; Reggiani, Francesca; Torricelli, Federica; Ciarrocchi, Alessia; Neri, Antonino; Bertolini, Federica; Dominici, Massimo; Filosso, Pier Luigi; Stella, Franco; Gibellini, Lara; De Biasi, Sara; Cossarizza, Andrea. - In: MOLECULAR CANCER. - ISSN 1476-4598. - 24:1(2025), pp. 1-28. [10.1186/s12943-024-02209-2]

Metabolically activated and highly polyfunctional intratumoral VISTA+ regulatory B cells are associated with tumor recurrence in early-stage NSCLC

Lo Tartaro, Domenico;Aramini, Beatrice
Methodology
;
Masciale, Valentina
Methodology
;
Lofaro, Francesco Demetrio;Neroni, Anita;Borella, Rebecca;Santacroce, Elena;Ciobanu, Alin Liviu;Samarelli, Anna Valeria;Boraldi, Federica;Quaglino, Daniela;Manzotti, Gloria;Reggiani, Francesca;Torricelli, Federica;Bertolini, Federica;Dominici, Massimo;Filosso, Pier Luigi;Gibellini, Lara;De Biasi, Sara;Cossarizza, Andrea
2025

Abstract

B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC. Our analysis revealed that TME contains diverse B cell clusters, including VISTA+ Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA+ Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-beta, IL-6, tumor necrosis factor (TNF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4+/CD8+ T lymphocytes in TME. The computational analysis of intercellular communications that links ligands to target genes, performed by NicheNet, predicted B-T interactions via VISTA-PSGL-1 axis. Colocalization analyses revealed that PSGL-1 T cells and VISTA+ B cells are adjacent in the TME. Notably, tumor infiltrating CD8+ T cells expressing PSGL-1 exhibited enhanced metabolism and cytotoxicity. In NSCLC patients, prediction analysis performed by PENCIL revealed the presence of an association between PSGL-1+CD8+ T cells and VISTA+ Bregs with lung recurrence. Our findings suggest a potential interaction between Bregs and T cells through the VISTA-PSGL-1 axis, that could influence NSCLC recurrence.
2025
24
1
1
28
Metabolically activated and highly polyfunctional intratumoral VISTA+ regulatory B cells are associated with tumor recurrence in early-stage NSCLC / Lo Tartaro, Domenico; Aramini, Beatrice; Masciale, Valentina; Paschalidis, Nikolaos; Lofaro, Francesco Demetrio; Neroni, Anita; Borella, Rebecca; Santacroce, Elena; Ciobanu, Alin Liviu; Samarelli, Anna Valeria; Boraldi, Federica; Quaglino, Daniela; Dubini, Alessandra; Gaudio, Michele; Manzotti, Gloria; Reggiani, Francesca; Torricelli, Federica; Ciarrocchi, Alessia; Neri, Antonino; Bertolini, Federica; Dominici, Massimo; Filosso, Pier Luigi; Stella, Franco; Gibellini, Lara; De Biasi, Sara; Cossarizza, Andrea. - In: MOLECULAR CANCER. - ISSN 1476-4598. - 24:1(2025), pp. 1-28. [10.1186/s12943-024-02209-2]
Lo Tartaro, Domenico; Aramini, Beatrice; Masciale, Valentina; Paschalidis, Nikolaos; Lofaro, Francesco Demetrio; Neroni, Anita; Borella, Rebecca; Sant...espandi
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