Abstract Background: The context of immune cell infiltrates within the tumor is associated with cancer prognosis. The type of immune cells and their activation state can provide mediators that either promote or inhibit tumor growth. A growing body of evidence suggest the presence of innate immune cells play a role in shaping early tumor growth. In attempts to gain insight into the immune networks that regulate tumorigenesis, we used genome wide expression datasets of patients with resected early stage non-small cell lung cancer (NSCLC) to identify immune-related genes associated with patient survival. Methods: Gene expression analysis was conducted on microarray datasets from 128 early-stage NSCLC adenocarcinoma resected tumor samples. Limiting analysis to immune-related genes, we identified a minimum gene set that is prognostic for lung adenocarcinoma and validated the gene signature in additional published microarray NSCLC datasets. Using pathway analysis and immunohistochemistry (IHC), we identified a role for mast cell-expressed IgE receptor beta subunit, MS4A2, in lung adenocarcinoma progression. Results: From an immune-related gene list, we identified a minimal gene signature that was able to separate patients into high or low-risk survival groups. This gene signature was shown to be prognostic for NSCLC adenocarcinoma in nine validation datasets (n=1264, hazard ratio 2.07, 95% confidence interval 1.69-2.53, p<0.0001). Pathway analysis of differentially expressed genes within high or low-risk survival subgroups reveals gene ontologies and immune signatures that are enriched for IgE receptor signaling and mast cells in patients with favourable prognosis. Univariate analysis shows that the IgE receptor complex genes, as well as mast cell specific protease, mast cell carboxypeptidase A, are highly prognostic for survival. We are currently using IHC of matched patient samples to validate receptor localization. Conclusion: By limiting gene expression analysis to immune-related genes, we identified a minimal gene set that indicate an important role for IgE receptor signaling and mast cells in favourable lung cancer prognosis. Our data highlights the importance of innate immune cells in shaping lung cancer development. Citation Format: Dalam Ly, Chang-Qi Zhu, Michael Cabanero, Ming-Sound Tsao, Li Zhang. Mast cell expressed FcεR beta subunit (MS4A2) is prognostic in lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A64.