Identification of a novel targetable cancer stem cell regulator promoting cancer progression and metastasis in non-small cell lung cancer

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Non-small cell lung cancer (NSCLC) accounts for around 85% of all lung cancer. The 5- year survival rate is about 14% for stage IIIA NSCLC, while it is about 5% for stage IIIB. However, once NSCLC has reached to the stage IV and metastasized to different places, it is very difficult to treat. The 5- year survival rate for stage IV NSCLC is just about 1%. Targeted therapy such as anti-EGFR or anti-ALK is the frontline treatment for advanced NSCLC with EGFR or ALK mutations, while platinum-based chemotherapy is the first line treatment for advanced NSCLC without targetable mutations. Interestingly, recent studies suggest that anti-PD1/PDL1 immunotherapy is a new and effective strategy for advanced NSCLC. While NSCLC patients initially show great benefit from these treatments, the response is only transient with relatively short duration likely due to acquiring resistant mechanisms. Identification of novel and effective therapeutic strategies is therefore an urgent need for advanced NSCLC with metastasis. A small cell population with CSC properties contributes to cancer initiation, progression and metastasis as well as drug resistance in various cancers such as NSCLC, but an effective strategy to eliminate CSCs is currently lacking, representing an unmet clinical need for CSC and NSCLC targeting. While CSCs possess immune escape properties, it is unclear how non-CSC cancer cells accounting for the majority of total cancer cell populations could also resist from immune cell attack. The goal of this study is to characterize a novel and unique CSC population in NSCLC and its regulatory mechanisms that can be harnessed for developing a novel effective strategy for advanced NSCLC and/or for overcoming the resistance to current standard of care. Our study identifies a novel druggable regulator localized in cell membrane for maintaining CSCs, cancer progression and metastasis of NSCLCs and its overexpression predicts poor survival outcome NSCLC patients. Genetically or pharmacologically targeting this newly identified regulator attenuates oncogenic signal for maintain CSC properties and immune escape leading to cancer progression and metastasis of NSCLC. We hypothesized that a unique cell population with CSC properties existed in cancer can transmit an oncogenic and immune escape signal to non-CSC cancer cells, thereby endowing bulk cancer cells with immune escape properties. We proposed three specific aims, which are highly supported by our innovative preliminary results, to further characterize the roles and underlying mechanisms of this novel regulator and its ligand as well as their targeting in regulating CSCs, progression and metastasis of NSCLC. Our proposal is highly original and significant, as we have proposed a breakthrough concept, identified a novel checkpoint blocker with CSC and immune escape properties and utilized cutting technologies including unbiased transcriptomics, Cas9/CRISPR editing, patient-derived organoids, patient derived xenograft (PDX) models, and humanized mice and genetic knockin mouse models with intact immunity to validate our provocative hypothesis and concept. Our study has revolutionized and significantly advanced our understanding of CSC and cancer-immune regulation, but also offers a new paradigm and strategy for targeting advanced NSCLC.