FAT1 upregulation is correlated with an immunosuppressive tumor microenvironment and predicts unfavorable outcome of immune checkpoint therapy in non-small cell lung cancer

Chao Chen; Yanling Li; Haozhen Liu; Mengying Liao; Jianyi Yang; Jixian Liu

doi:10.1016/j.heliyon.2024.e28356

FAT1 upregulation is correlated with an immunosuppressive tumor microenvironment and predicts unfavorable outcome of immune checkpoint therapy in non-small cell lung cancer

Heliyon. 2024 Mar 22;10(7):e28356. doi: 10.1016/j.heliyon.2024.e28356. eCollection 2024 Apr 15.

Authors

Chao Chen¹, Yanling Li², Haozhen Liu¹, Mengying Liao³, Jianyi Yang¹, Jixian Liu¹

Affiliations

¹ Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518035, China.
² Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, 518036, China.
³ Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, 518035, China.

Abstract

Background: Previous studies found that FAT1 was recurrently mutated and aberrantly expressed in multiple cancers, and the loss function of FAT1 promoted the formation of cancer-initiating cells in several cancers. However, in some types of cancer, FAT1 upregulation could lead to epithelial-mesenchymal transition (EMT). The role of FAT1 in cancer progression, which appears to be cancer-type-specific, is largely unknown.

Methods: QRT-PCR and immunochemistry were used to verify the expression of FAT1 in non-small cell lung cancer (NSCLC). QRT-PCR and Western blot were used to detect the influence of siFAT1 knockdown on the expression of potential targets of FAT1 in NSCLC cell lines. GEPIA, KM-plotter, CAMOIP, and ROC-Plotter were used to evaluate the association between FAT1 and clinical outcomes based on expression and clinical data from TCGA and immune checkpoint inhibitors (ICI) treated cohorts.

Results: We found that FAT1 upregulation was associated with the activation of TGF-β and EMT signaling pathways in NSCLC. Patients with a high FAT1 expression level tend to have a poor prognosis and hard to benefit from ICI therapy. Genes involved in TGF-β/EMT signaling pathways (SERPINE1, TGFB1/2, and POSTN) were downregulated upon knockdown of FAT1. Genomic and immunologic analysis showed that high cancer-associated fibroblast (CAF) abundance, decreased CD8⁺ T cells infiltration, and low TMB/TNB were correlated with the upregulation of FAT1, thus promoting an immunosuppressive tumor microenvironment (TME) which influence the effect of ICI-therapy.

Conclusion: Our findings revealed the pattern of FAT1 upregulation in the TME of patients with NSCLC, and demonstrated its utility as a biomarker for unfavorable clinical outcomes, thereby providing a potential therapeutic target for NSCLC treatment.

Keywords: FAT1; Immune checkpoint inhibitors; Non-small cell lung cancer; SERPINE1; Tumor microenvironment.