Abstract Despite decades of research, non-small cell lung carcinoma (NSCLC) remains one of the world's deadliest cancers. Approximately half of NSCLC cases are classified as lung adenocarcinomas (ADCA), in which KRAS, EGFR, and TP53 mutations are the predominant genetic drivers. Although patients with EGFR mutations are initially responsive to targeted therapies, drug resistance uniformly occurs within one year. KRAS mutant ADCA have proven even more intractable, as scant progress has been made in the development of therapeutics for this patient population. Recent breakthroughs in the field of immunotherapy have offered new hope for the management of NSCLC, but the clinical success of immunomodulatory agents will depend on a strong foundational knowledge of the immune cells that comprise the ADCA microenvironment. Activating mutations in KRAS and EGFR induce the aberrant function of numerous signaling pathways that may influence the host immune response in different ways. However, the discrete impact of KRAS and EGFR mutations on the immune composition of ADCA remains largely undefined. To address this question, we profiled the tumor microenvironments (TME) of four mouse models of ADCA: adenoviral Cre-infected KrasLSL-G12D and KrasLSL-G12D;Trp53Fl/Fl mice, as well as TetO-EgfrL858R;Ccsp-rtTA and TetO-EgfrL858R;T790M;Ccsp-rtTA mice. Lung specimens from tumor-bearing and control animals (n ≥ 5 per cohort) were harvested at multiple time points and subjected to histological assessment, gene expression analysis by qRT-PCR, and flow cytometric immunophenotyping, in which 23 markers were used to identify 12 unique cell types. The Kras subtype exhibited robust inflammation and expansion of both the lymphoid and myeloid cell compartments. In particular, significant increases were observed in the number of CD8+ T cells (3-fold), B cells (2.5-fold), and macrophages (16-fold). Although loss of Trp53 promoted tumor growth and malignancy, it had little effect on cytokine expression or immune cell recruitment into the Kras TME. In contrast, while EgfrL858R mutations produced similar total levels of inflammation, leukocyte recruitment into the Egfr TME was largely restricted to macrophage expansion (increased 8-fold). Introduction of the T790M resistance mutation to Egfr-mutant animals further amplified the macrophage dominant signal (14-fold). Expression of the cytokine IL-6 was correspondingly elevated in the Egfr but not Kras subtypes, a finding replicated in EGFR-transfected primary human endobronchial cells. Most notably, CD8+ cytotoxic T cell numbers were unaltered at all time points examined in the Egfr animals, a finding which raises concerns about the efficacy of most currently developed immune checkpoint blockers in EGFR patients. In summary, KRAS and EGFR mutations give rise to distinct immune responses that may require oncogene-specific immunotherapy regimens. Citation Format: Stephanie E. Busch, Mark L. Hanke, Kyoung Hee Kim, Julia Kargl, A. McGarry Houghton. EGFR and KRAS activation generate discrete inflammatory responses within the lung tumor microenvironment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3181. doi:10.1158/1538-7445.AM2015-3181