Background IFN-γ–inducible protein 16 (IFI16) is known to initiate STING pathway cascade, which leads to the downstream activation of various cytokines and chemokines that play important roles in enhancing tumor microenvironment immune responses. IFI16 activates STING signaling through the cooperation with cyclic GMP-AMP synthase (cGAS) through the detection of cytoplasmic DNA. Recently, we have shown that IFI16-dependent STING signaling upregulates effective anti-HER2 cellular immune responses in HER2 (+) breast cancer.1 The aim of this study was to assess the role of IFI16 levels with immune responses in metastatic cutaneous melanomas.
Methods Cutaneous melanoma datasets for mRNA expression were obtained from TCGA SKCM, GTEx, GSE7553, GSE15605, and GSE46517. The fraction of tumor-infiltrated immune cells (TIIC) was estimated by CIBERSORT. Patients from TCGA were divided into high- and low-IFI16 mRNA level groups, based on the highest and lowest quartiles. Extraction of Expression Module (EEM) analysis was performed. Correlations between variables were calculated with the Mann-Whitney U test with FDR corrections.
Results IFI16 mRNA levels were significantly upregulated in metastatic cutaneous melanomas (AJCC III/IV, n = 193) compared to normal skin (figure 1A, p < 0.0001), but significantly downregulated in metastatic versus primary melanomas in GSE7553 dataset (figure 1B, p = 0.016). High levels of IFI16 were significantly associated with poor prognosis in stage III/IV melanoma patients (figure 1C, p < 0.0001). The analysis of TIIC showed that M1 macrophage subset levels were significantly higher in the high-IFI16 vs low-IFI16 group (figure 1D, p = 0.0028). IFN-γ score was significantly higher in the high- vs low-IFI16 group in TCGA (figure 1E, p = 0.00051), GSE46516 (p = 0.00068), and GSE15605 (p = 0.026). EEM analysis showed that the activity scores of IFN-γ response were significantly higher in high-IFI16 vs low-IFI16 groups (p = 0.0048). Furthermore, data integration from EEM and differential expressed genes analysis identified 34 immune-related genes, of which chemokines CXCL10 and CXCL11 were significantly upregulated by the IFN-γ response pathway. The elevated CXCL10 and CXCL11 are known to enhance tumor immune microenvironment activity. CXCL10 and CXCL11 were significantly higher in high-IFI16 group in both the TCGA (figure 1F, p < 0.0001, p < 0.0001, respectively) and GSE46517 (p = 0.00016, p = 0.00062, respectively).
Conclusions High-IFI16 mRNA levels may represent predictive biomarkers of good prognosis in metastatic melanomas, whereby IFI16 mRNA levels were associated with significant immune responses through the upregulation of the IFN-γ pathway, M1 macrophage subset, and CXCL10/CXCL11.
Acknowledgements This work was supported by Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (D.S.B.H).
Ong LT, Lee WC, Ma S, Oguz G, Niu Z, Bao Y, Yusuf M, Lee PL, Goh JY, Wang P et al. IFI16-dependent STING signaling is a crucial regulator of anti-HER2 immune response in HER2+ breast cancer. Proc Natl Acad Sci U S A 2022;119(31):e2201376119.
Ethics Approval This study followed the principles in the Declaration of Helsinki. All human samples and clinical information for this study were obtained according to the protocol guidelines approved by Providence SJHC under SJHC Joint Institutional Review Board (IRB): IRB: JWCI-18-0401) and IRB: MORD-RTPCR-0995.
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