Integrated Clinical, Molecular and Immunological Characterization of Pulmonary Sarcomatoid Carcinomas Reveals an Immune Escape Mechanism That May Influence Therapeutic Strategies

Pulmonary sarcomatoid carcinoma (PSC) has highly aggressive biological behaviour and poor clinical outcomes, raising expectations for new therapeutic strategies. We characterized 179 PSC by immunohistochemistry, next-generation sequencing and in silico analysis using a deep learning algorithm with respect to clinical, immunological and molecular features. PSC was more common in men, older ages and smokers. Surgery was an independent factor (p < 0.01) of overall survival (OS). PD-L1 expression was detected in 82.1% of all patients. PSC patients displaying altered epitopes due to processing mutations showed another PD-L1-independent immune escape mechanism, which also significantly influenced OS (p < 0.02). The effect was also maintained when only advanced tumour stages were considered (p < 0.01). These patients also showed improved survival with a significant correlation for immunotherapy (p < 0.05) when few or no processing mutations were detected, although this should be interpreted with caution due to the small number of patients studied. Genomic alterations for which there are already approved drugs were present in 35.4% of patients. Met exon 14 skipping was found more frequently (13.7%) and EGFR mutations less frequently (1.7%) than in other NSCLC. In summary, in addition to the divergent genomic landscape of PSC, the specific immunological features of this prognostically poor subtype should be considered in therapy stratification.

Automated summary

Pulmonary sarcomatoid carcinoma (PSC) is a highly aggressive subtype of lung cancer with poor clinical outcomes. In this study, we characterized 179 PSC cases and identified clinical, immunological, and molecular features using various techniques. We found that PSC is more common in men, older individuals, and smokers. Surgery was associated with improved overall survival. PD-L1 expression was detected in the majority of patients, and altered epitopes due to processing mutations contributed to immune escape and decreased survival. Genomic alterations for which there are approved drugs were present in a subset of patients. MET exon 14 skipping was found to be more frequent compared to other non-small cell lung cancers. In conclusion, the unique genomic and immunological features of PSC should be considered in therapy stratification.