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

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Tumor-associated neutrophils (TANs) are abundant immune cells in tumors.
• Their regulation and function differ across cancer subtypes.
• TANs exhibit increased lifespan due to upregulated Bcl-xL, presenting a therapeutic target.

Purpose of the Study:

• Investigate TAN regulation and function in lung squamous cell carcinoma (LUSC).
• Evaluate the efficacy of Bcl-xL blockade in LUSC models.
• Assess the combination of Bcl-xL inhibition with chemotherapy in LUSC.

Main Methods:

• Utilized Rosa26^{LSL-Sox2-IRES-GFP}; Nkx2-1^fl/fl; Lkb1^fl/fl mouse models for LUSC.
• Administered BH3 mimetic to block Bcl-xL.
• Combined Bcl-xL blockade with carboplatin and paclitaxel chemotherapy.
• Analyzed neutrophil populations, Bcl-xL expression, and tumor progression.

Main Results:

• Increased TAN survival and Bcl-xL expression were observed in LUSC, similar to LUAD.
• Bcl-xL blockade alone did not significantly impact LUSC tumor progression.
• Chemotherapy increased circulating and tumor-infiltrating neutrophils and Bcl-xL levels.
• Combined Bcl-xL blockade and chemotherapy synergistically reduced Bcl-xL-high TANs and tumor progression.

Conclusions:

• Targeting TANs via Bcl-xL blockade has distinct outcomes in different lung cancer subtypes.
• Combining Bcl-xL inhibition with chemotherapy demonstrates efficacy in LUSC.
• BH3 mimetics show potential for repurposing in cancer therapy.