Computational immune profiling in lung adenocarcinoma reveals reproducible prognostic associations with implications for immunotherapy

Non-small cell lung cancer is one of the leading causes of cancer-related death in the world. Lung adenocarcinoma, the most common type of non-small cell lung cancer, has been well characterized as having a dense lymphocytic infiltrate, suggesting that the immune system plays an active role in shaping this cancer's growth and development. Despite these findings, our understanding of how this infiltrate affects patient prognosis and its association with lung adenocarcinoma-specific clinical factors remains limited. To address these questions, we inferred the infiltration level of six distinct immune cell types from a series of four lung adenocarcinoma gene expression datasets. We found that naive B cell, CD8+ T cell, and myeloid cell-derived expression signals of immune infiltration were significantly predictive of patient survival in multiple independent datasets, with B cell and CD8+ T cell infiltration associated with prolonged prognosis and myeloid cell infiltration associated with shorter survival. These associations remained significant even after accounting for additional clinical variables. Patients stratified by smoking status exhibited decreased CD8+ T cell infiltration and altered prognostic associations, suggesting potential immunosuppressive mechanisms in smokers. Survival analyses accounting for immune checkpoint gene expression and cellular immune infiltrate indicated checkpoint protein-specific modulatory effects on CD8+ T cell and B cell function that may be associated with patient sensitivity to immunotherapy. Together, these analyses identified reproducible associations that can be used to better characterize the role of immune infiltration in lung adenocarcinoma and demonstrate the utility in using computational approaches to systematically characterize tissue-specific tumor-immune interactions.