Abstract
IFNγ has antitumorigenic effects; however, the findings of IFNγ in promoting the tumor cell survival and inducing adaptive immune resistance via CD4+ T-cell loss and programmed death ligand 1 (PD-L1) upregulation challenge this concept. Lo and colleagues determined that IFNγ induces epithelial–mesenchymal transition (EMT) by regulating the turnover of miRNA in prostate cancer, emphasizing the duplicitous effects of IFNγ. IFIT5, an IFN-induced tetratricopeptide repeat (IFIT) family member, was found to form a complex with the exoribonuclease-XRN1 to process miRNA maturation. These findings unveil a new IFNγ–STAT1–IFIT5–miRNA–EMT pathway in prostate cancer progression. The biphasic effects of IFNγ in prostate cancer raise concerns about its therapeutic application, which need to be evaluated in future studies.
See related article by Lo et al., p. 1098
In this issue of Cancer Research, Lo and colleagues (1) describe an interesting observation wherein IFNγ induces epithelial–mesenchymal transition (EMT) in prostate cancer cells by regulating the degradation of precursor miRNAs through a complex between the known IFNγ-stimulated RNA-binding protein, interferon-induced tetratricopeptide 5 (IFIT5), and the exoribonuclease candidate XRN1 (IFIT5-XRN1). Their study emerged from research on the GTPase-activating protein, DAB2IP, which has long been a focus for this group. They found that IFNγ promotes EMT in prostate cancer cells through DAB2IP, which has been previously identified as an upstream regulator of EMT, and went on to profile the miRNAs and show that miR-363 expression and maturation are specifically regulated by DAB2IP and that IFIT5 is a key factor regulating miR-363 turnover. The authors next sought to further characterize the network among IFIT5, miRNA, and EMT in prostate cancer. They first discovered that miR-363 suppresses EMT by targeting Slug in prostate cancer cells and that IFIT5 recognizes the unique 5′-end overhanging structure of pre-miR-363 to target it for degradation. Because IFIT5 does not possess ribonuclease activity, the authors then demonstrated that IFIT5 alone is not sufficient in regulating miRNA maturation and degradation but needs to form a complex with exoribonuclease-XRN1 to promote miR-363 turnover. To expand the overall effects of the network they established, the authors further examined other miRNAs that could be regulated by IFNγ. Two additional miRNAs, miR-101 and miR-128, were also identified to be involved in the IFIT5-EMT process. Finally, they found that IFIT5 is inversely correlated with miR-363, miR-101, and miR-128 and positively correlated with EMT markers ZEB1, Slug, and vimentin in prostate cancer specimens. From benchwork to clinical validation, Lo and colleagues identified a network of immune factors, transcriptional factors, and miRNAs involved in prostate cancer progression and metastasis.
Although we now recognize that miRNA plays crucial roles in prostate cancer progression, regulation of miRNA expression remains largely unknown. After transcription, pre-miRNA undergoes nuclear and cytoplasmic processing to become mature miRNA. Alteration of mature miRNA expression occurs in many different ways, such as SNP, miRNA tailing, editing, methylation, and regulation of stability (2). XRN1 is a 5′-3′ exoribonuclease that predominantly degrades miRNAs after they have been decapped in cells. Lo and colleagues discovered for the first time that IFIT5 recruits XRN1 to form a unique miRNA complex with the 5′-end of pre-miRNA molecules. The reciprocal correlation of IFIT5 and miR-363 and miR-101 expression in prostate cancer specimens further supports the role of IFNγ signaling in miRNA regulation. Human IFNγ is predominantly from infiltrating immune cells and whether this correlation also exists in these cells in prostate tumors needs to be investigated in future studies. Nevertheless, this function of IFIT5 in miRNA processing provides a new piece of evidence that IFNγ signaling regulates miRNA maturation and turnover in prostate cancer.
Over the last few decades, our understanding of the role of IFNγ in cancer immunity has been evolving. Numerous studies have reported that IFNγ is an important cytokine that facilitates both the innate and adaptive immune systems. Initial induction of IFNγ significantly suppresses tumor growth via immune activation; however, it can also induce CD4+ T-cell apoptosis, alter the CD4:CD8 ratio, and subsequently impair secondary antitumor immune responses (3). As a type II IFN, IFNγ plays both pro- and antitumorigenic roles in immunoediting, a process that consists of immunosurveillance and tumor progression (4). IFNγ plays a role in all three phases of the immunoediting process: elimination, equilibrium, and escape. During the elimination phase, natural killer (NK) cells, NK T cells, CD8+, and CD4+ T cells secrete IFNγ, which then activates macrophages, dendritic cells, Th1 CD4+ helper T cells, and B cells that lead to complete tumor elimination, suggesting that IFNγ is predominantly antitumorigenic in the tumor environment during this phase. During the equilibrium phase, the immune system is able to maintain immune-mediated tumor dormancy. This phase is poorly understood, in part, because of technical challenges in establishing mouse models, but it is known that IFNγ is required for maintaining tumor dormancy by inducing cancer senescence. Finally, during the escape phase, tumor cells grow and expand through mechanisms including adaptive and acquired immune resistance (5). Recent studies suggest that IFNγ can upregulate the expression of programmed-death ligand 1 (PD-L1), a membrane-bound immune inhibitory molecule on the surface of tumor cells. Because PD-L1 binds to programmed cell death protein 1 (PD1) expressed on the activated CD8+ T cells and leads to apoptotic T-cell death, IFNγ signaling activation facilities tumor cells escaping from the antitumor CD8+ T-cell cytotoxicity through formation of the immunosuppressive tumor microenvironment, promotes tumor cell survival, and induces adaptive resistance (6). Therefore, IFNγ possibly plays a protumorigenic role during the tumor immunity escape stage. Although application of immunotherapy in prostate cancer lags behind that in other cancer types, several clinical trials testing immune checkpoint inhibitors in patients with prostate cancer have begun (7). The exact role of IFNγ in prostate cancer immunity remains to be determined and the study by Lo and colleagues brings up more concern into the prostate cancer immunotherapy arena by reinforcing the dual nature of IFNγ in prostate cancer progression.
Metastasis is the primary underlying cause of fatality in patients with prostate cancer. Bone metastases occur in more than 90% of patients with advanced prostate cancer and are associated with poor survival. For men with metastatic prostate cancer, only one-third survive for 5 years after diagnosis (8). There is an urgent need to unravel potential resistant mechanisms that perpetuate disease progression during effective androgen receptor blockade and to devise ways of targeting resistant pathways. EMT is believed to be a crucial step in the conversion of early-stage disease to invasive and metastatic cancer (9). Immortalized human mammary epithelial cells acquire the mesenchymal phenotype and express stem cell markers after induction of EMT (10). The aberrant expression and localization of E-cadherin, N-cadherin, vimentin, Wnt5A, and ZEB1 appears to be important in prostate cancer invasion and bone metastasis. Although strong evidence supports EMT as the essential step in the progression and metastasis of prostate cancer, difficulties in identifying migratory cancer cells have precluded confirmation of the occurrence of EMT in vivo for many years. Thus, better understanding of upstream EMT regulators is urgent and important in the clinical arena. EMT can be triggered by tumor-associated fibroblasts, immune cells, and secreted soluble factors, such as Wnt ligands, TGFβ, EGF, and hepatocyte growth factor. These factors and inflammatory cytokines can exert their effects through autocrine or paracrine systems. Slug, Snail, ZEB1, ZEB2, and Twist have been previously identified as classical EMT regulators. In their study, Lo and colleagues report that IFNγ induces EMT in prostate cancer cells by regulating expression of EMT regulators and markers such as ZEB1, Slug, and vimentin as well as miR-363, miR-101, and miR-128. The take-home message from this comprehensive study is that the administration of IFNγ might not benefit patients with prostate cancer and possibly cause some harmful side effects. Nevertheless, clinical evidence and clinical trials would be required before this could be considered as a conclusion.
Together, IFNγ signaling is still largely unfathomable in prostate cancer. Considering the classical role of IFNγ in cancer immunoediting, the possibility of its utility in prostate cancer immunetherapy arena should not be disregarded. Prostate cancer immunotherapy awaits rigorous investigation to define the real targets and pathways involved in the therapy. A better grasp of the detailed mechanisms that underlie the effects of IFNγ in prostate cancer immunoediting appears to be necessary. Lo and colleagues have identified a novel tumor-promoting IFNγ–STAT1–IFIT5–miRNA–EMT pathway in prostate cancer cells, suggesting that IFNγ might serve as a master regulator in controlling several downstream signaling pathways, such as JAK-STAT1, IFIT5, DAB2IP, and miRNA signaling leading to prostate cancer progression and metastasis through EMT, raising concerns about its clinical application.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
This commentary did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
- Received January 18, 2019.
- Accepted January 18, 2019.
- Published first March 15, 2019.
- ©2019 American Association for Cancer Research.