Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling Pathways

Simple Summary Pulmonary sarcomatoid carcinoma (PSC) is an aggressive subtype of non-small-cell lung cancer (NSCLC). It does not respond favorably to standard chemotherapy, and the response to PD-1/PD-L1 inhibitors remains modest. The introduction of new therapeutic approaches for this subtype is crucial. Our study demonstrates that PD-L1 expression was significantly higher in the epithelial component than in the sarcomatoid component. Expression of PD-L1 in both components was only seen in 32.1% of patients. However, the majority of PSC patients had at least one immune checkpoint expression in both components. Thus, combination immune checkpoint inhibition based on expression profiles may prove as a personalized and effective treatment strategy. This study also reveals a high rate of MET exon 14 skipping mutation (METex14) in PSC. METex14 selectively induced PD-L1 expression through MAPK or PI3K/Akt pathways. A combination of targeted therapies with immunotherapy in this population also warrants further investigation as a novel treatment approach. Immunotherapy has transformed lung cancer management, but PSC remains an aggressive subtype with a poor prognosis. This study investigates the differential expression of PD-L1 and alternative immune checkpoints (ICs; B7x, B7-H3, and HHLA2), and genetic alterations in PSCs. Tumor specimens of 41 PSC patients were evaluated. PD-L1, B7x, B7-H3, and HHLA2 were positive in 75.0%, 67.6%, 73.0%, and 91.9% of tumors, respectively. PD-L1 expression was significantly higher in the epithelial compared to the sarcomatoid component (median TPS: 50% vs. 0%, p = 0.010). Expression of PD-L1 in both components was only seen in 32.1% of patients. However, at least one IC was expressed in 92.9% of epithelial and 100% of sarcomatoid components. Furthermore, METex14 was detected in 19.5% of patients and was associated with a higher sarcomatoid percentage. Our preclinical studies revealed that METex14 induced PD-L1 expression via MAPK or PI3K/Akt pathways, and MET inhibitors decreased PD-L1 expression. Our findings demonstrate distinct expressions of ICs in PSC subcomponents. Thus, combination IC inhibition as a therapeutic strategy in PSC warrants further exploration. A high percentage of METex14 in PSC and its role in regulating PD-L1 expression reveal different therapeutic targets in this aggressive NSCLC subtype.

Automated summary

Pulmonary sarcomatoid carcinoma (PSC) is an aggressive subtype of non-small-cell lung cancer (NSCLC) that doesn't respond well to standard chemotherapy and PD-1/PD-L1 inhibitors. This study found that PD-L1 expression was higher in the epithelial component compared to the sarcomatoid component, and most PSC patients had at least one immune checkpoint expression in both components. Combination immune checkpoint inhibition based on expression profiles may be a personalized and effective treatment strategy.