More importantly, in a Huh-7 xenograft mouse model, GPC3CAR-T cells significantly reduced the tumour burden companied with the secretion of high levels of IFN-γ.
Bone marrow MDSC were induced to differentiate in vitro into tumor MDSC-like cells by treating with IFN-γ, IL-13, and GM-CSF for 48 h. This treatment significantly elevated Arg1 and Nos2 levels, activated the T cell-suppressive function of MDSC, increased VDR expression 50-fold, and made the MDSC responsive to 1,25(OH)<sub>2</sub>D treatment.
This was associated with enhanced T-cell exhaustion, and severely attenuated T-cell antitumor effector responses including reduced expression of IFN-γ and perforin at the tumor site.
GLPG1690 decreased irradiation-induced C-C motif chemokine ligand-11 in tumors and levels of interleukin-9, interleukin-12p40, macrophage colony-stimulating factor and interferon γ in adipose tissue adjacent to the tumor.
Under this circumstance, the PD-1 molecule on the human T lymphocyte surface is in contact with the PD-L1 molecule on the human tumor cells and, thus, the formatin of the PD-L1/PD-1 pathway in the tumor microenvironment.Treatment with anti-PD-1 monoclonal antibody (mAb) significantly inhibited the growth of both CDX and PDX tumors, but not non-human NCG models (without allogeneic human PBMCs and IFN-γ) .
The therapeutic reconstruction released IFNγ at the LRR site and eliminated cancer cells, significantly decreased tumor burden (P<0.05), and increased survival by 33% (P<0.05) compared to sham reconstruction.
Altogether, this study unveils a prometastatic role of the IFNγ pathway via a new mechanism of action, which raises concerns about its clinical application.<b>Significance:</b> A unique IFIT5-XRN1 complex involved in the turnover of specific tumor suppressive microRNAs is the underlying mechanism of IFNγ-induced epithelial-to-mesenchymal transition in prostate cancer.<i>See related commentary by Liu and Gao, p. 1032</i>.
This review focuses on the diverse positive and negative roles of IFN-γ in immune cell activation and differentiation leading to protective immune responses, as well as the paradoxical effects of IFN-γ within the tumor microenvironment that determine the ultimate fate of that tumor in a cancer-bearing individual.
Cytokines associated with Th1 immune response (IL-12 [p70], IFN-γ, GM-CSF) and eosinophil recruitment (eotaxin-1, IL-5, and IL-13) were significantly elevated in tumors of ω3-fed mice.
Recent results reveal that ferroptosis mediates the tumor suppressive activity of interferon gamma secreted by CD8<sup>+</sup> T cells in response to immune checkpoint blockade, suggesting the immune system may function in part through ferroptosis to prevent tumorigenesis (Wang et al., 2019).
Depletion of NK cells in α-GalCer-treated mice showed a lower frequency of IFN-γ-producing CD4<sup>+</sup> and CD8<sup>+</sup> T cells in the tumor and prevented the α-GalCer-induced tumor growth.
Selection of tumor cells by exposure to tumor-specific T cells identified components of the interferon-γ (IFN-γ) receptor (IFNGR) signaling pathway, and tumor cell killing by cytotoxic T cells was shown to be in large part mediated by the pro-apoptotic effects of IFN-γ.
In C57Bl/6 mice, we showed that peritumoral plasmid IL-12 electrotransfer combined with tumor pIRE treatment induced tumor regression correlating with a local secretion of IL-12 and IFN-γ.
Furthermore, the quantity of interferon gamma released from HUVEC-DOC-administered mice was significantly higher than the other three groups, and enhanced CD8<sup>+</sup> T cell infiltration was observed more frequently in tumors excised from HUVEC-DOC-treated mice.
Moreover, this process was related to donor-derived T/B cells by improving the immune microenvironment in the tumor, as demonstrated by elevated levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-6, IL-16, chemokine (C-X-C motif) ligand 10 (CXCL10), and CXCL11 and decreased levels of IL-10 and IL-4 at tumor sites.
Here, we first isolated and identified sphere-forming cells in tumor tissue from four GC patients and then analyzed T cell responses induced by monocyte-derived dendritic cells (DCs) loaded with total mRNA of sphere-forming cells in terms of interferon-gamma (IFN-γ) gene expression and specific cytotoxicity.
Mechanistically, IFNγ derived from immunotherapy-activated CD8<sup>+</sup> T cells and radiotherapy-activated ATM independently, yet synergistically, suppresses SLC7A11, a unit of the glutamate-cystine antiporter xc<sup>-</sup>, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control.
FACS was used to determine the frequencies of Tregs, MDSCs, CD4<sup>+</sup> IFN-γ<sup>+</sup> T cells, and CTLs in the tumors and spleens of the mice. mRNA levels of the transcription factors T-bet and FOXP3 and cytokines IFN-γ, TNF-α, TGF-β, and IL-10 were also determined by real-time RT-PCR.
Despite its critical role in the defense against microbial infection and tumor development, little is known about the range of nucleotide and haplotype variation at IFN-γ, or the evolutionary forces that have shaped patterns of diversity at this locus.
During pregnancy, CD56<sup>dim</sup> and CD56<sup>bright</sup> NK cells displayed enhanced functional responses to both infected and tumor cells, with increased expression of degranulation markers and elevated frequency of NK cells producing IFN-γ.
Analysis of TCGA dataset revealed that the mRNA expression levels of PD-L1 and PD-L2, the IFN-γ gene signature and the CD8 T effector gene signature were significantly upregulated in MSI-H tumors compared with MSI-L/MSS tumors.