MET Amplification Attenuates Lung Tumor Response to Immunotherapy by Inhibiting STING

Abstract

Immune checkpoint blockade (ICB) has revolutionized cancer therapy. However, the response of patients to ICB is difficult to predict. Here, we examined 81 patients with lung cancer under ICB treatment and found that patients with MET amplification were resistant to ICB and had a poor progression-free survival. Tumors with MET amplifications had significantly decreased STING levels and antitumor T-cell infiltration. Furthermore, we performed deep single-cell RNA sequencing on more than 20,000 single immune cells and identified an immunosuppressive signature with increased subsets of XIST- and CD96-positive exhausted natural killer (NK) cells and decreased CD8+ T-cell and NK-cell populations in patients with MET amplification. Mechanistically, we found that oncogenic MET signaling induces phosphorylation of UPF1 and downregulates tumor cell STING expression via modulation of the 3′-UTR length of STING by UPF1. Decreased efficiency of ICB by MET amplification can be overcome by inhibiting MET. Significance: We suggest that the combination of MET inhibitor together with ICB will overcome ICB resistance induced by MET amplification. Our report reveals much-needed information that will benefit the treatment of patients with primary MET amplification or EGFR–tyrosine kinase inhibitor resistant-related MET amplification. This article is highlighted in the In This Issue feature, p. 2659

Pteridium spp. and Bovine Papillomavirus: Partners in Cancer

“…The second way involves their immune suppressive properties, which may facilitate the persistence of oncogenic viruses like BPV and HPV and may also allow early neoplastic lesions to evade immunological surveillance and develop into overt cancers ( 27 ). Latorre and collaborators showed that ptaquiloside is able to inactivate natural killer (NK) cells ( 106 ), which are key players in innate immunity and are essential for defending the host against viral infections and against cancer ( 107 ). When activated, NK cells are able to recognize and destroy neoplastic cells and virus-infected cells.…”

The combination of gene hyperamplification and PD-L1 expression as a biomarker for the clinical benefit of tislelizumab in gastric/gastroesophageal junction adenocarcinoma

“…Our study found HA mainly occurred in genes involved in the cell cycle and RTK-RAS-PI3K pathways, which are known to be involved in tumorigenesis. Previous studies have reported that amplifications of cell cycle driver genes and RTK-RAS-PI3K pathway genes, such as CCND1, MDM2, MET and VEGF-A, were associated with a lack of response to or poor survival benefit with anti-PD(L)-1 treatment [38][39][40][41][42][43][44]. In addition, reduced interferon response, low T cell abundance, poor T cell activity and a more immunosuppressive tumor microenvironment (enriched TGF-β signaling, hypoxia signaling) were observed in tumors with amplified genes in these two pathways, suggesting that hyperamplification in cell cycle/RTK-RAS-PI3K pathways may be a key point to drive anti-PD(L)-1 resistance through inducing both an immunosuppressive tumor microenvironment and malignancy hallmarks [40,41,[44][45][46][47].…”

Clinical significance of STING expression and methylation in lung adenocarcinoma based on bioinformatics analysis

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