Type I Interferon Regulates a Coordinated Gene Network to Enhance Cytotoxic T Cell–Mediated Tumor Killing

Abstract

Type I interferons (IFN), which activate many IFN-stimulated genes (ISG), are known to regulate tumorigenesis. However, little is known regarding how various ISGs coordinate with one another in developing antitumor effects. Here, we report that the ISG UBA7 is a tumor suppressor in breast cancer. UBA7 encodes an enzyme that catalyzes the covalent conjugation of the ubiquitin-like protein product of another ISG ( ISG15 ) to cellular proteins in a process known as "ISGylation. " ISGylation of other ISGs, including STAT1 and STAT2, synergistically facilitates production of chemokinereceptor ligands to attract cytotoxic T cells. These gene-activation events are further linked to clustering and nuclear relocalization of STAT1/2 within IFN-induced promyelocytic leukemia (PML) bodies. Importantly, this coordinated ISG-ISGylation network plays a central role in suppressing murine breast cancer growth and metastasis, which parallels improved survival in patients with breast cancer. These fi ndings reveal a cooperative IFN-inducible gene network in orchestrating a tumor-suppressive microenvironment. SIGNIFICANCE:We report a highly cooperative ISG network, in which UBA7-mediated ISGylation facilitates clustering of transcription factors and activates an antitumor gene-expression program. These fi ndings provide mechanistic insights into immune evasion in breast cancer associated with UBA7 loss, emphasizing the importance of a functional ISG-ISGylation network in tumor suppression.

cGAS-STING pathway in cancer biotherapy

“…Therefore, understanding underlying mechanisms among innate immune responses, adaptive immune responses and the cGAS-STING pathway is crucial. Type I IFNs attract cytotoxic T cells to tumor bed [45] and trigger type I T helper cell (Th1) responses [22]. Moreover, type I IFNs make dendritic cells (DCs) mature and presenttumor specific antigens to CD4 + and protective CD8 + T cells [46].…”

“…As stimuli, endogeneous retrovirus, DNA damage, genomic instability, damaged mitochondria, dying cells, exosomes, DNA viruses, retroviruses and bacteria contribute to the production of dsDNA. Herpes simplex virus-1 (HSV-1), vesicular stomatitis virus (VSV) and porcine circovirus type 2 (PCV2), as DNA viruses, promote IFN by activating cGAS-STING signaling pathway [ 21 – 23 ]. Besides, endogeneous retrovirus RNAs triggers a cascade wave of signaling to upregulate INF production by cGAS-STING pathway [ 24 ].…”

Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B

“…At the mechanistic level, IFN-I-related immune escape has been previously associated with the upregulation in cancer (stem) cell of (i) PD-L1 and LGALS9 23 , (ii) nitric oxide synthase 2 (NOS2), which favors the recruitment of regulatory cells 51 , and (iii) Serpinb9, which inhibits granzyme B activity and thus CD8 + T cell cytotoxicity 52 . Intriguingly, by integrating ATAC-seq and RNA-seq data, we found upregulation, in CD44H IFN-CSCs, of serpins and downregulation of Uba7, a tumor suppressor ISG which codes for a protein able to attract effector T cells 53 . Whether these factors play a major role in protecting CSC from immune attack remains to be established.…”

Proteomic Profiling of Protease-Primed Virus-Permissive Caco-2 Cells Display Abortive-Interferon Pathway and Deregulated Thromboinflammatory SERPINS

“…Multiple signaling pathways that are targeted by viruses tend to converge on preventing the phosphorylation, dimerization, and nuclear translocation of the transcription factors IRF-3/7 (Soham et al, 2020). The coordinated ISG-ISGylation network has been recently shown to play a central role in providing anti-tumor immunity (Fan et al, 2020). IFNs activate the JAK-STAT pathway, which triggers induction of many IFN-stimulated genes (ISGs), and not all of these have been completely characterized (Stark et al, 2012;Borden et al, 2019).…”