Immunesurveillance of Lung Cancer by Natural Killer Cells Abstract Lung cancer is the leading cause of cancer related mortality in both men and women in the United States. Non-small cell lung cancer (NSCLC) constitutes 80% of all lung cancers and immune checkpoint blockade has emerged as an effective therapeutic strategy, but only 20% of NSCLC patients respond to these agents. Among veterans both the rate of incidence and the rate of mortality are twice higher than the entire population, making this an urgent unmet clinical need among veterans particularly for those who do not respond to current therapies. NK cells are innate lymphoid cells fundamental to host defense against viral infections and malignancies. In humans, low NK cell cytotoxicity in peripheral blood correlates with increased cancer risk. Conversely, NK cell infiltration into tumor tissue is associated with better patient prognosis in multiple malignancies, including NSCLC. Our preliminary data show that depletion of NK cells in a genetic mouse model of lung cancer significantly promotes tumor progression, increases tumor burden and decreases survival of mice, demonstrating a critical role for NK-mediated immune surveillance in lung tumorogenesis Cell adhesion molecule 1 (CADM1) belongs to the immunoglobulin superfamily of calcium independent cell adhesion molecules, capable of both homophilic and heterophilic interactions. Interestingly, CADM1 expression is frequently lost in 20-40% of non-small cell lung cancers (NSCLC) either by loss of heterozygosity or promoter hypermethylation. However, the mechanism(s) by which CADM1 regulates tumor progression is not known. CADM1 is one of seven proteins in mammals that undergoes an unusual glycosylation known as polysialylation. The other notable Polysialic acid (polysia) carrier is the protein CD56 expressed on NK cells. Polysia is a unique carbohydrate structure known for its potent anti-adhesive properties preventing two polysialylated proteins from interacting with each other. On the other hand, a cell surface protein known as CRTAM (Class-I MHC-restricted T-cell-associated molecule) was identified as the strongest heterophilic binding partner of CADM1. CRTAM is expressed on activated NK cells and the CADM1/CRTAM axis has been implicated in immune surveillance. Our recent study showed that, in cells expressing CADM1, its induction renders cancer cells susceptible to NK-mediated cytotoxicity. Inhibition of CADM1 expression promoted metastasis by evading NK mediated immune surveillance. In contrast, restoring CADM1 in cells with promoter hypermethylation was sufficient to make cancer cells susceptible to NK-mediated toxicity, suggesting that suppressing CADM1 may be an immune evasive strategy of tumors. Consistently, increased expression of CADM1 directly correlated with prolonged patient survival and inversely correlated with higher stage and metastatic disease. We show that polysialylation of CADM1 on tumor cells modulates their su...