Lung epithelial lineage-specific factors in the control of immune system evasion genes in tumor cells

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ABSTRACT Cancer cells that are capable of escaping host immune system defenses typically adopt more aggressive behaviors. Novel immunotherapies targeting these mechanisms are now successfully employed in the treatment of many cancers, including highly aggressive forms of lung cancer. However, these therapies do not limit cancer progression in all patients, emphasizing a need for more effective immune-modulating drugs. Ultimately, however, to develop these new treatments, scientists first need to understand the mechanisms by which cancer cells control the expression of immune evasion genes, also called immune checkpoints. Lineage-specific transcription factors that establish cell fate during organ development also play functions in cancer as lineage- specific tumor drivers. In the lung, the lineage-specific transcription factor NKX2-1 (TTF1), which is critical for epithelial development, shows pro- and anti-oncogenic activity in lung cancer depending on cell context. Moreover, its expression in cancer cells has been shown to shape the tumor immune microenvironment. We have recently reported that NKX2-1-AS1, an antisense long noncoding RNA overlapping the NKX2-1 promoter, is abundantly expressed in human fetal and adult lung epithelial cells, and its levels are further increased in lung cancer, matching NKX2-1 patterns. Furthermore, we found that relative levels of NKX2-1 and NKX2-1-AS1 vary considerably among different cancer cell populations and that NKX2-1 and NKX2-1-AS1 have opposing effects on the expression of the immune checkpoint gene PD-L1. In preliminary analysis, we discovered that NKX2-1 and NKX2-1AS1 also have opposing effects on the control of various other genes involved in immune system evasion. These results highlight a novel mechanism by which lung cancer cells can balance host-immune responses while controlling intrinsic cancer cell properties. Based on these findings, we hypothesize that lung cancer cells, through the lung epithelial lineage-specific factors NKX2-1 and NKX2-1-AS1, control multiple immune checkpoint genes and the escape of cancer cells from the immune system attack. We will test this hypothesis in two Aims. In Aim 1, we will define in vitro the molecular mechanism by which NKX2-1-AS1 limits the expression of genes involved in immune system evasion in lung cancer cell lines through the interaction with NKX2-1 and other key transcription factors such as STAT3. In Aim 2, we will test, using a co-culture system, the functional effect of different epithelial NKX2-1-AS1 and NKX2-1 expression ratios on the activation of T-cells. These studies have the potential to impact the field of pulmonary medicine significantly and transform the way we understand how lung epithelial-lineage factors control pulmonary immune responses, laying the foundation for new and more effective anti-cancer therapies.