Abstract
Lkb1 and Pten loss in the mouse lung causes fully penetrant SCC with features of the human disease.
Major finding: Lkb1 and Pten loss in the mouse lung causes fully penetrant SCC with features of the human disease.
Concept: High PD-L1 expression in Lkb1;Pten-null tumors implicates immune evasion in lung SCC tumorigenesis.
Impact: PD-1/PD-L1 blockade may be an effective strategy for treatment of lung SCC.
Lung squamous cell carcinoma (SCC) is the second leading cause of lung cancer–related deaths and has no approved targeted therapies to date. Although several molecular alterations associated with lung SCC have been recently identified, mouse models that can recapitulate this disease and facilitate preclinical testing are lacking. Xu and colleagues found that lung-specific inactivation of the tumor suppressors Lkb1 and Pten in mice led to the formation of tumors strongly resembling human lung SCC with 100% penetrance. Lkb1;Pten-null tumors were characterized by canonical squamous marker expression and prominent keratinization and displayed a gene expression profile similar to that of the basal subtype of human lung SCC, but did not share the same gene expression, metabolite, or signaling profiles as Kras-driven lung adenocarcinoma (ADC), indicating that Lkb1;Pten-null tumors exhibit a purely squamous phenotype. Moreover, unlike Kras-driven ADCs, which primarily contain tumor-associated macrophages, Lkb1;Pten-null tumors were highly enriched for tumor-associated neutrophils and Tregs, which are known to suppress the immune system and cause peripheral immune tolerance in lung cancer patients. Consistent with this finding suggesting a potential role for immune suppression in lung SCC tumorigenesis, tumor-infiltrating T cells within highly expressed the negative T-cell costimulatory molecule programmed cell death protein 1 (PD-1) and Lkb1;Pten-null tumor cells had high cell surface expression of the PD-1 ligand PD-L1. Notably, Lkb1;Pten-null tumors contained a distinct tumor-propagating cell (TPC) population that was able to serially propagate tumors that retained squamous characteristics, and both these cells and putative human TPCs from lung SCC patient-derived xenografts had the most abundant levels of PD-L1. Collectively, these findings establish a mouse model of lung SCC that can be used to evaluate potential therapeutic strategies and provide a rationale for evaluating modulators of the immune microenvironment in lung SCC, such as anti-PD-1/PD-L1 immunotherapy.