Analyzing whole-exome tumor sequencing data from 16 patients with melanoma, the researchers found multiple copy-number alterations that led to the loss of key IFNγ pathway genes in 12 ipilimumab nonresponders.
Our objective in this study was to investigate whether polymorphisms in the regulatory regions of IL10, IL6 and IFNgamma genes are associated with the development of primary cutaneous melanoma and/or the prognosis of this tumour.
It was found that TNFA -238 GA, TGFB1 -509 CT, -800 GG, IFNG +874 AT, IL6 -174 GG, IL10 -1082 GA genotypes were significantly decreased, while TNFA -238 AA, -857 CC, TGFB1 -509 TT, IFNG +874 AA, IL6 -174 CC, IL10 -1082 AA, -819 TT, -592 AA genotypes were significantly increased, in MM.
Despite progressive increases in the T-helper type 1 (Th1)-inducing gene (IL-12), RT-PCR indicated impaired Th1 or cytotoxic T-cell response (decreased IFN-γ) in MM.
Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ.
Therefore, a phase I clinical trial was performed of autologous <i>in vitro</i> expanded iNKT cells in stage IIIB-IV melanoma.<b>Experimental Design:</b> Residual iNKT cells [<0.05% of patient peripheral blood mononuclear cell (PBMC)] were purified from autologous leukapheresis product using an antibody against the iNKT cell receptor linked to magnetic microbeads. iNKT cells were then expanded with CD3 mAb and IL2 <i>in vitro</i> to obtain up to approximately 10<sup>9</sup> cells.<b>Results:</b> Expanded iNKT cells produced IFNγ, but limited or undetectable IL4 or IL10.
Analyzing melanoma cell lines (n = 46, applying next-generation targeted sequencing and single nucleotide polymorphism arrays) as well as available genomic data sets from The Cancer Genome Atlas (TCGA) tumor tissue samples (cutaneous melanoma n = 367, lung squamous cell carcinoma n = 501, bladder urothelial carcinoma n = 408, breast invasive carcinoma n = 768, colorectal adenocarcinoma n = 257), we demonstrate that the frequent chromosomal losses of the tumor suppressor CDKN2A in melanoma and other tumor entities enhance the susceptibility to IFNγ resistance by concomitant deletion of the JAK2 gene (odds ratio = 223.17, 95% confidence interval = 66.91 to 1487.38, two-sided P = 7.6×10-46).
Our results demonstrate that melanoma responses to IFNγ are heterogeneous, frequently downregulated in immune checkpoint inhibitor-naïve melanoma and potentially predictive of response to immunotherapy.
These protective effects were long-lasting in Panc02-induced tumor development, but not in melanoma. iDC-vaccination impacted the immune status of the hosts by greatly increasing the percentage of CD8<sup>+</sup> T-cells, and natural killer (NK)1.1<sup>+</sup> cells, that express granzyme B associated with Lamp-1 and IFN-γ.
In this study, we demonstrated an increase in B16F10 melanoma growth and a decrease in the proportion of IFN-γ- and TNF-α-secreting tumor-infiltrating CD8<sup>+</sup> T cells in B cell-specific PTEN-deficient mice in which Bregs were expanded.
In the melanoma model derived from patient DT, we applied cryopreserved short-term autologous mixed lymphocyte-tumor cell cultures (MLTCs) in combination with an IFN-gamma enzyme-linked immunospot (ELISPOT) assay to cDNA expression screening.
Incubation of melanoma cell lines with interferon-gamma (IFN-γ) increased phosphatidylserine and calreticulin exposure, but not in the IFN-γ-resistant cell line Lu-1205.
A combination of plasmid DNAs encoding murine fetal liver kinase 1 extracellular domain, murine interleukin-12, and murine interferon-gamma inducible protein-10 leads to tumor regression and survival in melanoma-bearing mice.
Based on these considerations, a novel class of cancer destroying adenoviruses have been produced, cancer terminator viruses (CTVs), in which cancer-specific replication is controlled by the progression-elevated gene-3 promoter and replicating viruses produce a second transgene encoding an apoptosis-inducing and immunomodulatory cytokine, either melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) or interferon-γ.
Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFNγ) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity.
The insertion of the IFN gamma gene into melanoma cells may be useful either for active immunization against melanoma or for the generation of TIL to be used in adoptive immunotherapy.