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<p>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<sup>+</sup> Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA<sup>+</sup> Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-β, IL-6, tumor necrosis factor (TNF), and granulocyte–macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4<sup>+</sup>/CD8<sup>+</sup> 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&#xa0;T cells and VISTA<sup>+</sup> B cells are adjacent in the TME. Notably, tumor infiltrating CD8<sup>+</sup> 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<sup>+</sup>CD8<sup>+</sup> T cells and VISTA<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月14日

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  • Domenico Lo Tartaro,
  • Beatrice Aramini,
  • Valentina Masciale,
  • Nikolaos Paschalidis,
  • Francesco Demetrio Lofaro,
  • Anita Neroni,
  • Rebecca Borella,
  • Elena Santacroce,
  • Alin Liviu Ciobanu,
  • Anna Valeria Samarelli,
  • Federica Boraldi,
  • Daniela Quaglino,
  • Alessandra Dubini,
  • Michele Gaudio,
  • Gloria Manzotti,
  • Francesca Reggiani,
  • Federica Torricelli,
  • Alessia Ciarrocchi,
  • Antonino Neri,
  • Federica Bertolini,
  • Massimo Dominici,
  • Pier Luigi Filosso,
  • Franco Stella,
  • Lara Gibellini,
  • Sara De Biasi,
  • Andrea Cossarizza

摘要

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)-β, 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.