Characterizing the molecular and immunological features of lung micropapillary adenocarcinoma.

Abstract

e21036 Background: Micropapillary adenocarcinoma (MPC) is one of the most aggressive histologic subtypes of lung adenocarcinoma (ADC). Although the incidence of MPC predominant ADC is low, nearly half of ADCs contain a minor proportion of MPC, which could contribute to poor prognosis in these patients. Comprehensive analysis of genetic and immunological features of ADC with different MPC contents would help better understand cancer biology of this ADC subtype and direct future treatments. Methods: We performed panel next-generation sequencing (NGS) of 425 cancer-related genes for a discovery cohort of 43 ADC patients whose tumors were microdissected to separate MPC and non-MPC regions and a reference cohort of 113 ADC patients with unknown ADC histologic subtypes. MPC-enriched mutations were identified by comparing tumors with different original MPC contents within these cohorts, which was then confirmed using a validation cohort of 183 ADC patients. Staining of immunological markers was also conducted for MPC samples from the discovery cohort to investigate their tumor microenvironment. Results: We found that ADC tumors with higher MPC contents/similarities tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). In addition, genetic alterations in transcription termination factor 1 ( TTF1), brain-specific angiogenesis inhibitor 3 ( BAI3), mammalian target of rapamycin ( MTOR), cyclin-dependent kinase inhibitor 2A ( CDKN2A), and CDKN2A were found to be enriched in MPC using the discovery and reference cohorts, which could then be cross-validated using the validation cohort. Tumors with higher MPC content were associated with elevated infiltration of CD4+, CD8+ and FOXP3+ T cells, especially at the peritumor regions. Higher percentage of PD-L1+ tumor cells were also found to be correlated with higher MPC content, suggesting of more immunosuppression in MPC predominant tumors than low MPC tumors. Conclusions: We identified multiple novel MPC-enriched genetic changes that could help understand the nature of MPC. MPC predominant tumors tended to have higher levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, making it a potential candidate for immunotherapy, especially the combination therapy of anti-PD-1/PD-L1 drugs and anti-CTLA-4 drugs, which could inhibit PD-1/PD-L1 pathway and FOXP3+ Treg cells simultaneously.