Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Lung squamous cell carcinoma (SCC) presents a significant unmet clinical need due to inadequate current treatments.
• Understanding the molecular drivers and microenvironment of SCC is crucial for developing effective therapies.

Purpose of the Study:

• To establish a preclinical mouse model that accurately recapitulates human lung SCC.
• To investigate the cellular and molecular characteristics of this model, including its tumor microenvironment and potential therapeutic targets.

Main Methods:

• Biallelic inactivation of Lkb1 and Pten genes in mouse lung epithelial cells.
• Histological and gene expression analysis to compare with human SCC.
• Flow cytometry and orthotopic transplantation assays to identify and characterize tumor-propagating cells (TPCs).
• Analysis of immune cell populations and PD-L1 expression in the model and human SCC samples.

Main Results:

• The Lkb1;Pten null (LP) mouse model developed SCC with histology and gene expression similar to the basal subtype of human SCC.
• LP tumors exhibited an immune microenvironment enriched in tumor-associated neutrophils.
• SCA1(+)NGFR(+) fractions were identified as enriched for TPCs capable of serial transplantation.
• TPCs in the LP model and NGFR(+) cells in human SCCs demonstrated high expression of PD-L1, indicating a potential immune evasion strategy.

Conclusions:

• The Lkb1;Pten null mouse model serves as a valuable tool for studying lung SCC pathogenesis and evaluating immunotherapies.
• The identification of PD-L1 expression on TPCs suggests that targeting the PD-1/PD-L1 axis may be a viable therapeutic strategy for SCC.
• This model provides insights into the role of the tumor microenvironment, particularly neutrophils, in SCC development and progression.