Abstract
We developed a human melanoma model using the HT168-M1 cell line to induce IFN-α2 resistance in vitro (HT168-M1res), which was proven to be maintained in vivo in SCID mice. Comparing the mRNA profile of in vitro cultured HT168-M1res cells to its sensitive counterpart, we found 79 differentially expressed genes (DEGs). We found that only a 13-gene core of the DEGs was stable in vitro and only a 4-gene core was stable in vivo. Using an in silico cohort of IFN-treated melanoma tissues, we validated a differentially expressed 9-gene core of the DEGs. Furthermore, using an in silico cohort of immune checkpoint inhibitor (ICI)-treated melanoma tissues, we tested the predictive power of the DEGs for the response rate. Analysis of the top four upregulated and top four downregulated genes of the DEGs identified WFDC1, EFNA3, DDX10, and PTBP1 as predictive genes, and analysis of the “stable” genes of DEGs for predictive potential of ICI response revealed another 13 genes, out of which CDCA4, SOX4, DEK, and HSPA1B were identified as IFN-regulated genes. Interestingly, the IFN treatment associated genes and the ICI-therapy predictive genes overlapped by three genes: WFDC1, BCAN, and MT2A, suggesting a connection between the two biological processes.
Highlights
IntroductionType I and type II IFNs are cytokines primarily produced by virus-infected cells to initiate innate immune responses
Type I IFNs signal through IFNAR1/2 heterodimeric receptors, activate Tyk2 and JAK1, and phosphorylate STAT1/2, which form complexes with IRF9, translocate to the nucleus, and activate expression of interferon-stimulated genes (ISG)
We described differentially expressed genes associated with IFN resistance for in vitro cultured human melanoma cells
Summary
Type I and type II IFNs are cytokines primarily produced by virus-infected cells to initiate innate immune responses. They share many biological functions, they have distinct receptors. Type I IFNs signal through IFNAR1/2 heterodimeric receptors, activate Tyk and JAK1, and phosphorylate STAT1/2, which form complexes with IRF9, translocate to the nucleus, and activate expression of interferon-stimulated genes (ISG). Type II IFN (IFN-γ) has a heterodimeric receptor, IFNGR1/2, which, upon ligand binding, activates JAK1/2 and phosphorylates STAT1, resulting in nuclear translocation and activation of the ISGs. IFNRG1/2 can activate alternative signaling pathways as well (STAT4, ERK1/2, Pyk, or CRK1) [1]. There are over 2000 IFN-regulated genes (IRGs) known today, including growth factors (like VEGF, FGF, and ECGF), chemokines (such as MIB, EBI1, and IL-8), adhesion molecules (i.e., ICAM1, CD47, and ALCAM), MHC class I and II, apoptosis regulators (such as FAS and CASP4/8), signaling molecules (like IFI16 and STAT1/2), and several transcription factors (including IRF1-7, ISGF3G, MPB1, PBX3, and, interestingly, HIF1α)
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