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<p>Tumor-associated neutrophils (TANs) represent a large fraction of immune cells in tumors, but how their regulation and function vary in distinct cancer subtypes remains unknown. In <i>Kras</i><sup><i>LSL-G12D/WT</i></sup><i>; p53</i><sup><i>fl/fl</i></sup> mouse models of lung adenocarcinoma (LUAD), TANs have an increased lifespan compared to normal neutrophils. Specifically, TANs upregulate the anti-apoptotic protein Bcl-xL, whose blockade by a BH3 mimetic selectively kills ageing TANs and diminishes tumor growth. Here, we have addressed this issue in lung squamous cell carcinoma (LUSC) using the <i>Rosa26</i><sup><i>LSL-Sox2-IRES-GFP</i></sup><i>; Nkx2-1</i><sup><i>fl/fl</i></sup><i>; Lkb1</i><sup><i>fl/fl</i></sup> mouse model, where we demonstrate increased TAN survival with a rise in Bcl-xL similarly to LUAD. However, unlike in LUAD, inhibiting Bcl-xL alone was insufficient to alter tumor progression in LUSC. After carboplatin and paclitaxel treatment, a combination chemotherapy used in human LUSC, we detected increased neutrophils in circulation, spleen and tumors, and increased Bcl-xL in neutrophils and TANs. Bcl-xL blockade decreased the pool of Bcl-xL-high TANs and synergized with chemotherapy. Altogether, our results suggest distinct outcomes for targeting TANs in different tumor types and reinforce the concept of repurposing BH3 mimetics against cancer.</p>

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Bcl-xL blockade targets neutrophils and synergizes with chemotherapy in lung squamous cell carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月31日

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  • Abdullah Mayet,
  • Beatrice Parma,
  • Déborah Lécuyer,
  • Amaury Defruit,
  • Sarika Rana,
  • Anita Bodac,
  • Pieter Demetter,
  • Sébastien Denanglaire,
  • Abbie S Ireland,
  • Mariana Brandão,
  • Thierry Berghmans,
  • Fabienne Andris,
  • Stanislas Goriely,
  • Jean Yannis Perentes,
  • Trudy G Oliver,
  • Etienne Meylan

摘要

Tumor-associated neutrophils (TANs) represent a large fraction of immune cells in tumors, but how their regulation and function vary in distinct cancer subtypes remains unknown. In KrasLSL-G12D/WT; p53fl/fl mouse models of lung adenocarcinoma (LUAD), TANs have an increased lifespan compared to normal neutrophils. Specifically, TANs upregulate the anti-apoptotic protein Bcl-xL, whose blockade by a BH3 mimetic selectively kills ageing TANs and diminishes tumor growth. Here, we have addressed this issue in lung squamous cell carcinoma (LUSC) using the Rosa26LSL-Sox2-IRES-GFP; Nkx2-1fl/fl; Lkb1fl/fl mouse model, where we demonstrate increased TAN survival with a rise in Bcl-xL similarly to LUAD. However, unlike in LUAD, inhibiting Bcl-xL alone was insufficient to alter tumor progression in LUSC. After carboplatin and paclitaxel treatment, a combination chemotherapy used in human LUSC, we detected increased neutrophils in circulation, spleen and tumors, and increased Bcl-xL in neutrophils and TANs. Bcl-xL blockade decreased the pool of Bcl-xL-high TANs and synergized with chemotherapy. Altogether, our results suggest distinct outcomes for targeting TANs in different tumor types and reinforce the concept of repurposing BH3 mimetics against cancer.