Dysregulation in IFN-γ signaling and response: the barricade to tumor immunotherapy

Han, Jiashu; Wu, Mei; Liu, Ziwen

doi:10.3389/fimmu.2023.1190333

Cited by 15 publications

(4 citation statements)

References 198 publications

(221 reference statements)

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“…( Figures 3B, E, F and Supplementary Figure S6 ) Notably, these alterations in the T cell infiltration profile, which promote anti-tumor immune responses, were more pronounced in the MS group. In terms of anti-tumor immune cytokines, the exercise intervention groups, particularly MS group, exhibited a noteworthy elevation in interferon-γ (IFN-γ) levels in comparison to the control group, which represents an enhanced immune response ( 43 ). ( Figure 3G ) Elevated levels of perforin (PF) and granzyme B, the primary molecules responsible for T-cell-mediated cytotoxicity ( 44 ), were detected in both the LS and MS groups, aligning with the previously observed increase in apoptosis following exercise interventions.…”

Section: Resultsmentioning

confidence: 99%

Exercise sensitizes PD-1/PD-L1 immunotherapy as a hypoxia modulator in the tumor microenvironment of melanoma

Yan,

Jiang,

Huang

et al. 2023

Front. Immunol.

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IntroductionHypoxia is associated with unfavorable prognoses in melanoma patients, and the limited response rates of patients to PD-1/PD-L1 blockade could be attributed to the immunosuppressive tumor microenvironment induced by hypoxia. Exercise offers numerous benefits in the anti-tumor process and has the potential to alleviate hypoxia; however, the precise mechanisms through which it exerts its anti-tumor effects remain unclear, and the presence of synergistic effects with PD-1/PD-L1 immunotherapy is yet to be definitively established.MethodsWe established a B16F10 homograft malignant melanoma model and implemented two distinct exercise treatments (low/moderate-intensity swim) based on the mice’s exercise status. The specific function manner of exercise-induced anti-tumor effects was determined through RNA sequencing and analysis of changes in the tumor microenvironment. Furthermore, moderate-intensity swim that exhibited superior tumor suppression effects was combined with Anti-PD-1 treatment to evaluate its in vivo efficacy in mouse models.ResultsExercise intervention yielded a considerable effect in impeding tumor growth and promoting apoptosis. Immunohistochemistry and RNA sequencing revealed improvements in tumor hypoxia and down-regulation of hypoxia-related pathways. Cellular immunofluorescence and ELISA analyses demonstrated a notable increase of cytotoxic T cell amount and a decrease of regulatory T cells, indicating an improvement of tumor immune microenvironment. In comparison to Anti-PD-1 monotherapy, tumor suppressive efficacy of exercise combination therapy was found to be enhanced with improvements in both the hypoxic tumor microenvironment and T cell infiltration.ConclusionExercise has the potential to function as a hypoxia modulator improving the tumor immune microenvironment, resulting in the promotion of anti-tumor efficacy and the facilitation of biologically safe sensitization of PD-1/PD-L1 immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Exercise sensitizes PD-1/PD-L1 immunotherapy as a hypoxia modulator in the tumor microenvironment of melanoma

Yan,

Jiang,

Huang

et al. 2023

Front. Immunol.

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“…With respect to the ρ 0 D5/ρ 0 D5LM comparison, interferon-alpha and chronic inflammation together create a tumour permissive microenvironment, not necessarily directly related to EMT, which only had an NES of 1.13 ( Supplementary Table 1 ). This tumour permissive environment is further enhanced by metastatic cancer cells hijacking the interferon gamma response ( 37 ), which is also enriched in ρ 0 D5 cells. Increased cholesterol metabolism in ρ 0 D5 cells provides metastatic cancer cells with much needed cholesterol as a structural element of membranes.…”

Section: Discussionmentioning

confidence: 99%

Residual OXPHOS is required to drive primary and metastatic lung tumours in an orthotopic breast cancer model

Herst,

Carson,

Lewthwaite

et al. 2024

Front. Oncol.

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BackgroundFast adaptation of glycolytic and mitochondrial energy pathways to changes in the tumour microenvironment is a hallmark of cancer. Purely glycolytic ρ0 tumour cells do not form primary tumours unless they acquire healthy mitochondria from their micro-environment. Here we explored the effects of severely compromised respiration on the metastatic capability of 4T1 mouse breast cancer cells.Methods4T1 cell lines with different levels of respiratory capacity were generated; the Seahorse extracellular flux analyser was used to evaluate oxygen consumption rates, fluorescent confocal microscopy to assess the number of SYBR gold-stained mitochondrial DNA nucleoids, and the presence of the ATP5B protein in the cytoplasm and fluorescent in situ nuclear hybridization was used to establish ploidy. MinION nanopore RNA sequence analysis was used to compare mitochondrial DNA transcription between cell lines. Orthotopic injection was used to determine the ability of cells to metastasize to the lungs of female Balb/c mice.ResultsOXPHOS-deficient ATP5B-KO3.1 cells did not generate primary tumours. Severely OXPHOS compromised ρ0D5 cells generated both primary tumours and lung metastases. Cells generated from lung metastasis of both OXPHOS-competent and OXPHOS-compromised cells formed primary tumours but no metastases when re-injected into mice. OXPHOS-compromised cells significantly increased their mtDNA content, but this did not result in increased OXPHOS capacity, which was not due to decreased mtDNA transcription. Gene set enrichment analysis suggests that certain cells derived from lung metastases downregulate their epithelial-to-mesenchymal related pathways.ConclusionIn summary, OXPHOS is required for tumorigenesis in this orthotopic mouse breast cancer model but even very low levels of OXPHOS are sufficient to generate both primary tumours and lung metastases.

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“…To determine the specific role of IFN and its signaling pathways in tumor progression, it is proposed to investigate its effects in a wide range of cellular, temporal, and molecular settings [54,57]. Furthermore, it has been suggested to explore alterations in different parts of the IFNγ signaling pathway-both in the IFNGR/JAK/STAT axis and in the expression levels of various downstream target genes [58].…”

Section: Irf1 Tumor-promoting Functionsmentioning

confidence: 99%

Roles of Interferon Regulatory Factor 1 in Tumor Progression and Regression: Two Sides of a Coin

Perevalova,

Gulyaeva,

Pustylnyak

2024

IJMS

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IRF1 is a transcription factor well known for its role in IFN signaling. Although IRF1 was initially identified for its involvement in inflammatory processes, there is now evidence that it provides a function in carcinogenesis as well. IRF1 has been shown to affect several important antitumor mechanisms, such as induction of apoptosis, cell cycle arrest, remodeling of tumor immune microenvironment, suppression of telomerase activity, suppression of angiogenesis and others. Nevertheless, the opposite effects of IRF1 on tumor growth have also been demonstrated. In particular, the “immune checkpoint” molecule PD-L1, which is responsible for tumor immune evasion, has IRF1 as a major transcriptional regulator. These and several other properties of IRF1, including its proposed association with response and resistance to immunotherapy and several chemotherapeutic drugs, make it a promising object for further research. Numerous mechanisms of IRF1 regulation in cancer have been identified, including genetic, epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms, although their significance for tumor progression remains to be explored. This review will focus on the established tumor-suppressive and tumor-promoting functions of IRF1, as well as the molecular mechanisms of IRF1 regulation identified in various cancers.

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Dysregulation in IFN-γ signaling and response: the barricade to tumor immunotherapy

Cited by 15 publications

References 198 publications

Exercise sensitizes PD-1/PD-L1 immunotherapy as a hypoxia modulator in the tumor microenvironment of melanoma

Exercise sensitizes PD-1/PD-L1 immunotherapy as a hypoxia modulator in the tumor microenvironment of melanoma

Residual OXPHOS is required to drive primary and metastatic lung tumours in an orthotopic breast cancer model

Roles of Interferon Regulatory Factor 1 in Tumor Progression and Regression: Two Sides of a Coin

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