Abstract Oncogenic K-ras mutations found in ∼ 30% of all non-small cell lung cancers are associated with chemoresistance and poor prognosis. Using a K-ras induced lung cancer mouse model, CC-LR, we previously showed that K-ras mutant lung tumors have intrinsic inflammatory characteristics with activation of NF-kB pathway, release of inflammatory cytokines IL-6, and activation of the IL-6 responsive transcription factor STAT3. We have further shown that IL-6/STAT3 pathway, and IL-17 producing CD4 helper T cells (Th17 cells) through their main cytokine, IL-17A, play critical roles in promotion of lung cancer in this model. IL-22 is another effecter molecule secreted by Th17 cells which is highly expressed in our K-ras mutant mouse model. IL-22 is a unique cytokine, which seems to act exclusively on nonhematopoietic cells, with basal IL-22R expression in the epithelial cells and fibroblast, and mostly signals through STAT3 pathway. Here we found that genetic ablation of IL-22 in CC-LR mice (CC-LR/IL22-KO mice), causes significant reduction in lung surface tumor numbers by ∼54% (2.1-fold). Histopathological analysis of lung sections confirmed a reduction in number and size of tumors in CC-LR/IL22-KO mice, which was associated with significantly lower tumor cell proliferation, angiogenesis and STAT3 activation. IL-22 ablation also reduced the numbers of inflammatory cells in bronchoalveolar lavage fluid, and decreased the expression of pro-tumor inflammatory cytokines such as IL-6, IL-17 and TNFα. This was associated with increased expression of anti-tumor Th1 cells -specific transcription factor (Tbet) and their activation markers, IFNγ, and GZB, and decreased expression of pro-tumor Th17- (RORγ) and T regulatory (FOXP3+) specific transcription factors. Recent studies have shown an association between IL-22 and stem-cell like properties in colon cancer. In lung cancer, cell populations expressing NANOG, SOX2, Oct4 and/or aldehyde dehydrogenase activity are enriched with stemness properties. Interestingly, in CC-LR/IL22-KO mice we found significant reduction in expression of these stemness genes. Thus, we conclude that IL-22 promotes K-ras mutant lung tumorigenesis by inducing a pro-tumor inflammatory microenvironment with proliferative and angiogenic properties as well as protecting stemness characteristic in epithelial/tumor cells. Therefore, we propose pharmacological targeting of IL-22 as a potential therapeutic strategy in combination with conventional cytotoxic therapy, immune check point blockade, or other targeted therapies (e.g. MEK inhibition) for lung cancer patients with K-ras mutation. Citation Format: Nasim Khosravi, Amber M. Cumpian, Soudabeh Daliri, Cynthia De La Garza, Mauricio S. Caetano, Seyed Javad Moghaddam. Impact of Interleukin-22 on K-ras mutant lung tumor microenvironment and stemness properties. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4398.