Statin shapes inflamed tumor microenvironment and enhances immune checkpoint blockade in non–small cell lung cancer

Abstract

Immune checkpoint blockade (ICB) therapy has achieved breakthroughs in the treatment of advanced non-small cell lung cancer (NSCLC). Nevertheless, the low response due to immuno-cold tumor microenvironment (TME) largely limits the application of ICB therapy. Based on the glycolytic/cholesterol synthesis axis, a stratification framework for EGFR wild-type NSCLC was developed to summarize the metabolic features of immuno-cold and immuno-hot tumors. The cholesterol subgroup displays the worst prognosis in immuno-cold NSCLC with significant enrichment of the cholesterol gene signature, indicating targeting cholesterol synthesis is essential for the therapy for immuno-cold NSCLC. Statin, the inhibitor for cholesterol synthesis, can suppress the aggressiveness of NSCLC in vitro and in vivo and also drastically reverse immuno-cold to an inflamed phenotype in vivo which exhibited a higher response to ICB therapy. Moreover, both our in-house data and meta-analysis further support that statin can significantly enhance ICB efficacy. In terms of preliminary mechanisms, statin could transcriptionally inhibit PD-L1 expression and induce ferroptosis in NSCLC cells. Overall, we reveal the significance of cholesterol synthesis in NSCLC and demonstrate the improved therapeutic efficacy of ICB in combination with statin.These findings could provide a innovative clinical insight to treat NSCLC patients with immuno-cold tumors.

The role of lipid metabolic reprogramming in tumor microenvironment

“…A high level of cholesterol is essential for the proliferation and metastasis of tumor cells to fulfill the requirement for membrane structure. cholesterol also stabilizes PD-L1 on the tumor cell surface, thus inhibiting tumor immunity 87 . In addition, high levels of cholesterol in the TME also affect the phenotype and activity of tumor-associated immune cells 88 .…”

“…The function, characteristics, and expression of lipid metabolism-related markers in different types and stages of tumors are summarized in Table 1 . Notably, an enhanced expression of cholesterol-related genes is associated with low immunotherapy response, which indicates their potential value as immunotherapy biomarkers 87 .…”

SECTM1 is upregulated in immuno-hot tumors and predicts immunotherapeutic efficacy in multiple cancers

“… 42 , 43 The inflamed subtype is considered to be immuno-hot, and excluded and deserted subtypes are considered to be immuno-cold. 44 …”

Protocol to identify novel immunotherapy biomarkers based on transcriptomic data in human cancers

“…The inflamed subtype is considered to be immuno-hot, and both excluded and deserted subtypes are considered to be immuno-cold. 21 Note: If the candidate gene could be used as a pan-cancer biomarker, the association between the candidate gene and MSI status should be validated in gastrointestinal tumors. Note: This step is usually done without any programming software, just using widely used softwares such as Office-Excel, GraphPad Prism, and SPSS.…”