The untold story of IFN-γ in cancer biology

Kursunel, M. Alper; Esendağlı, Güneş

doi:10.1016/j.cytogfr.2016.07.005

Cited by 152 publications

(116 citation statements)

References 192 publications

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“…44,45 Here, we show that CPMV stimulates the IFN- γ pathway as early as 24 h post intratumoral treatment and that this response is maintained over at least 4 days (later time points were not considered in our Luminex studies). In fact, the CPMV-induced IFN- γ predominant response increases and expands over time to include inflammatory cytokines like Eotaxin, GM-CSF, and IL-12 (these players are specific to CPMV, and elevation was not observed for any of the TMV formulations).…”

Section: Discussionmentioning

confidence: 85%

In Situ Vaccination with Cowpea vs Tobacco Mosaic Virus against Melanoma

et al. 2018

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Cancer immunotherapy approaches have emerged as novel treatment regimens against cancer. A particularly interesting avenue is the concept of in situ vaccination, where immunostimulatory agents are introduced into an identified tumor to overcome local immunosuppression and, if successful, mount systemic antitumor immunity. We had previously shown that nanoparticles from cowpea mosaic virus (CPMV) are highly potent in inducing long-lasting antitumor immunity when used as an in situ vaccine in various tumor mouse models. Here we asked whether the nanoparticles from tobacco mosaic virus (TMV) could also be applied as an in situ vaccine and, if so, whether efficacy or mechanism of immune-activation would be affected by the nanoparticle size (300 × 18 nm native TMV vs 50 × 18 nm short TMV nanorods), shape (nanorods vs spherical TMV, termed SNP), or state of assembly (assembled TMV rod vs free coat protein, CP). Our studies indicate that CPMV, but less so TMV, elicits potent antitumor immunity after intratumoral treatment of dermal melanoma (B16F10 using C57BL/6 mice). TMV and TMVshort slowed tumor growth and increased survival time, however, at significantly lower potency compared to that of CPMV. There were no apparent differences between TMV, TMVshort, or the SNP indicating that the aspect ratio does not necessarily play a role in plant viral in situ vaccines. The free CPs did not elicit an antitumor response or immunostimulation, which may indicate that a multivalent assembly is required to trigger an innate immune recognition and activation. Differential potency of CPMV vs TMV can be explained with differences in immune-activation: data indicate that CPMV stimulates an antitumor response through recruitment of monocytes into the tumor microenvironment (TME), establishing signaling through the IFN-γ pathway, which also leads to recruitment of tumor-infiltrated neutrophils (TINs) and natural killer (NK) cells. Furthermore, the priming of the innate immune system also mounts an adaptive response with CD4+ and CD8+ T cell recruitment and establishment of effector memory cells. While the TMV treatment also lead to the recruitment of innate immune cells as well as T cells (although to a lesser degree), key differences were noted in cyto/chemokine profiling with TMV inducing a potent immune response early on characterized by strong pro-inflammatory cytokines, primarily IL-6. Together, data indicate that some plant viral nanotechnology platforms are more suitable for application as in situ vaccines than others; understanding the intricate differences and underlying mechanism of immune-activation may set the stage for clinical development of these technologies.

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Section: Discussionmentioning

confidence: 85%

In Situ Vaccination with Cowpea vs Tobacco Mosaic Virus against Melanoma

et al. 2018

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“…Given the known importance of IFN‐γ in anti‐tumor immunity, several research studies and clinical trials have considered IFN‐γ as a therapeutic target. The various modalities of IFN‐γ treatment have not provided significant survival advantage over conventional cancer therapy . Tumor cells unresponsive to IFN‐γ account for one of the mechanisms underlying the failure of IFN‐γ treatment in cancer.…”

Section: Discussionmentioning

confidence: 99%

IFN‐γ‐mediated inhibition of lung cancer correlates with PD‐L1 expression and is regulated by PI3K‐AKT signaling

Gao

Yang

Cai

et al. 2018

Intl Journal of Cancer

165

127

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IFN-γ plays a crucial role in anti-tumor responses and also induces expression of PD-L1, a well-established inhibitor of anti-tumor immune function. Understanding how molecular signaling regulates the function of IFN-γ might improve its anti-tumor efficacy. Here, we show that the tumor expression of IFN-γ expression alone has no significant prognostic value in patients with locally advanced lung adenocarcinoma. Surprisingly, patients with tumors expressing both IFN-γ and PD-L1 have the best prognosis compared to those with tumors expressing IFN-γ or PD-L1 alone. Transcriptome analysis demonstrated that tumor tissues expressing IFN-γ display gene expression associated with suppressed cell cycle progression and expansion. Unexpectedly this profile was observed in PD-L1 but not PD-L1- tumors. The current concept is that PD-L1 functions as a shield protecting tumor cells from cytolytic T cell (CTL)-mediated anti-tumor progression. However, our data indicate that PD-L1 expression in the presence of IFN-γ might serve as biomarker for the sensitivity of tumors to the inhibitory effect of IFN-γ. Mechanistic analysis revealed that in lung adenocarcinoma cells IFN-γ-induced activation of JAK2-STAT1 and PI3K-AKT pathways. The activation of JAK2-STAT1 is responsible for the anti-proliferative effect of IFN-γ. Inhibition of PI3K downregulated PD-L1 expression and enhanced the anti-proliferative effect of IFN-γ, suggesting that blockade of PI3K might maximize the IFN-γ-mediated anti-tumor effect. Our findings provide evidence for crosstalk between JAK2-STAT1 and PI3K-AKT pathways in response to IFN-γ in lung adenocarcinoma and have implications for the design of combinatorial targeted therapy and immunotherapy for the treatment of lung adenocarcinoma.

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“…Interferon gamma plays key roles in the immune responses and in antitumor mechanisms [33,34]. IFN-γ+874T>A polymorphisms are associated with viral and bacterial infections, which result in chronic inflammation and carcinogenic [35–37].…”

Section: Discussionmentioning

confidence: 99%

“…Mechanisms underlying the association are not known. However, for anti-tumor activity, IFN-γ plays a central role in the recognition and elimination of transformed cells through its cytostatic, pro-apoptotic, and immune-provoking effects [33]. …”

Section: Discussionmentioning

confidence: 99%

Subsets of Inflammatory Cytokine Gene Polymorphisms are Associated with Risk of Carcinogenic Liver Fluke Opisthorchis viverrini-Associated Advanced Periductal Fibrosis and Cholangiocarcinoma

Surapaitoon

Suttiprapa²,

Mairiang

et al. 2017

Korean J Parasitol

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Opisthorchis viverrini infection induces chronic inflammation, and a minor proportion of infected individuals develop advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA). Inflammatory cytokines and/or their gene polymorphisms may link to these biliary pathologies. We therefore investigated associations among cytokine gene polymorphisms and cytokine production in 510 Thai cases infected with O. viverrini who presented with APF+ or APF−, as established by abdominal ultrasonography as well as in patients diagnosed with CCA. Levels of pro-inflammatory and anti-inflammatory cytokines were determined in culture supernatants after stimulation of peripheral blood mononuclear cells (PBMCs) with O. viverrini excretory-secretory (ES) products. Pro-inflammatory cytokines, IL-1β, IL-6, IFN-γ, LT-α, and TNF-α were significantly increased in CCA patients compared with non-CCA (APF− and APF+) cases. Polymorphisms in genes encoding IL-1β-511C/T, IL-6-174G/C, IFN-γ +874T/A, LT-α +252A/G, and TNF-α −308G/A were then investigated by using PCR-RFLP or allele specific-PCR (AS-PCR) analyses. In the CCA cases, LT-α +252A/G and TNF-α −308G/A heterozygous and homozygous variants showed significantly higher levels of these cytokines than the wild type. By contrast, levels of cytokines in wild type of IFN-γ +874T/A were significantly higher than the variants in CCA cases. IFN-γ +874T/A polymorphisms were associated with advanced periductal fibrosis, whereas IL-6 −174G/C polymorphisms were associated with CCA. To our knowledge, these findings provide the first demonstration that O. viverrini infected individuals carrying several specific cytokine gene polymorphisms are susceptible to develop fibrosis and CCA.

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The untold story of IFN-γ in cancer biology

Cited by 152 publications

References 192 publications

In Situ Vaccination with Cowpea vs Tobacco Mosaic Virus against Melanoma

In Situ Vaccination with Cowpea vs Tobacco Mosaic Virus against Melanoma

IFN‐γ‐mediated inhibition of lung cancer correlates with PD‐L1 expression and is regulated by PI3K‐AKT signaling

Subsets of Inflammatory Cytokine Gene Polymorphisms are Associated with Risk of Carcinogenic Liver Fluke Opisthorchis viverrini-Associated Advanced Periductal Fibrosis and Cholangiocarcinoma

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