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

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 Kras^LSL-G12D/WT; p53^fl/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 Rosa26^{LSL-Sox2-IRES-GFP}; Nkx2-1^fl/fl; Lkb1^fl/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.

Duke Scholars

Author Trudy G Oliver Pharmacology & Cancer Biology