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6ThiodG induces anti-tumor immunity in SCLC

ABSTRACT: There are few effective treatments for small cell lung cancer (SCLC). We explored a major dependency of small cell lung cancer as a therapeutic target. Nearly all of SCLCs have telomerase activity and they are dependent on this enzyme for their ability to continuously divide. We utilized a nucleoside analog, 6-Thio-2’-deoxyguanosine (6TdG), that is preferentially recognized by telomerase to promote telomere dysfunction. Low and intermittent doses of 6TdG inhibited tumor growth and metastasis from the primary tumors. Anti-tumor activity of 6TdG was associated with decrease in cancer initiation cell (CIC) markers L1CAM/CD133 and increase in visibility to innate and adaptive immunity. Mechanistically, 6TdG depleted CICs and induced type-I interferon signaling by activating tumor STING. We confirmed the functional essential role of CIC markers L1CAM/CD133 in SCLC tumor initiation. We also observed dramatic synergy between 6TdG and irradiation in both syngeneic and humanized SCLC models that was dependent on immune cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE225018 | GEO | 2023/12/11

REPOSITORIES: GEO

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Project description:Background Epithelial to mesenchymal transition (EMT) endows cancer cells with pro-metastatic properties, which appear most effective when cells enter an intermediate hybrid (H) state, characterized by integrated mesenchymal (M) and epithelial (E) traits. The reasons for this advantage are poorly known and, especially, it is totally unexplored whether the interplay between H-cells and NK cells could have a role. Here we characterize the pro-metastatic mechanics of Non-small Cell Lung Cancer (NSCLC) H-cells and their subset of cancer-initiating cells (CICs), dissecting crucial interactions with NK cells. Methods Human lung cancer cell lines and sub-lines representative of E, M, or H states, assessed by proteomics, were analysed in vivo for their tumor-forming and disseminating capabilities. Interactions with NK cells were investigated in vitro using migration assays, cytotoxic degranulation assays and evaluation of CD133+ CICs modulation after co-culture, and validated in vivo through NK cell neutralization assays. Correlation between EMT status, NK cell infiltration, and survival data, was evaluated in a cohort of surgically resected NSCLC cases (n=79). Results We demonstrated that H-cells, have limited dissemination capability but show highest potential to initiate metastases in vivo. This property was related to their ability to escape NK cell surveillance. Mechanistically, H-cells expressed low levels of NK-attracting chemokines (CXCL1 and CXCL8), generating poorly infiltrated metastases. Accordingly, proteomics and GO enrichment analysis of E, H, M cell lines showed that the related secretory processes could change during EMT. Furthermore, H-CICs uniquely expressed high levels of the inhibitory ligand B7-H3, which protected H-CIC from NK cell-mediated clearance. In vivo neutralization assays confirmed that, indeed, the pro-metastatic properties of H-cells are poorly controlled by NK cells. Finally, the analysis of patients revealed that detection of hybrid phenotypes associated with low NK infiltration in NSCLC clinical specimens could identify a subset of patients with poor prognosis. Conclusions Our study demonstrates that H-cells play a central role in the metastatic spread in NSCLC. Such pro-metastatic advantage of H-cells is supported by their altered interaction with NK cells and by the critical role of B7H3 in preserving their H-CIC component, indicating B7H3 as a potential target in combined NK-based therapies.

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6ThiodG induces anti-tumor immunity in SCLC

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