June 16, 2024

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PNAS: The STING signal inside the tumor affects its tolerance to immunotherapy

PNAS: The STING signal inside the tumor affects its tolerance to immunotherapy

 

PNAS: The STING signal inside the tumor affects its tolerance to immunotherapy.  The lack or loss of tumor antigenicity is the key to its immune escape ability and resistance to T cell immunotherapy.

There is evidence that the activation of interferon gene (STING) signal stimuli in tumor cells can enhance their antigenicity by triggering type I IFN-mediated autocrine and paracrine.

Although inhibition of this pathway has been found to be therapeutically beneficial in melanoma and other tumor types, the underlying mechanism remains unclear.

In this regard, James J. Mulé’s team from Moffitt Cancer Center tried to study whether the inhibitory effect of STING was partially epigeneticly regulated, and whether it affected the resistance of melanoma to T cell immunotherapy. The relevant results were published in the recent “PNAS” magazine.


Previous studies have found that in a large number of human melanoma cell lines, the expression of STING and cGAS proteins is down-regulated to varying degrees (STING is about 50%, cGAS is about 35%).

In order to determine the role of DNA methylation in melanoma STING and cGAS silencing, the authors used the Illumina MethylationEPIC BeadChip microarray platform to perform genome-wide DNA methylation analysis on 16 human melanoma cell lines, and evaluated 18 STING Methylation changes in CpG probes.

At the same time, the author performed immunoblotting analysis on each cell line and performed quantitative processing to determine the degree of correlation between the β value in each probe and the expression of STING protein. Studies have confirmed that there is a negative correlation between STING hypermethylation and protein expression (Pearson r = -0.51).

In addition, the beta heat maps of these CpG probes identified three different subclasses based on their STING protein expression. In the cell lines WM266-4, WM239A, WM2032 and 888-MEL lacking STING, hypermethylation was found, and the two CpG probes (cg16983159 and cg08321103) of WM1361A also showed hypermethylation (β value> 0.7).

The above results indicate that the loss of STING may be mediated by genetic and/or epigenetic changes (such as histone modifications or factors involving microRNAs).

PNAS: The STING signal inside the tumor affects its tolerance to immunotherapy PNAS: The STING signal inside the tumor affects its tolerance to immunotherapy
(Figure 1. The epigenetic modification of STING in melanoma is negatively correlated with its expression)

In order to evaluate whether DNA demethylation can restore STING expression and function, the authors next used 6 melanoma cell lines lacking STING (STING promoter hypermethylation): WM1361A, WM2032, WM239A, WM266-4, 888- MEL and SBCL-2 were studied.

And add DNA methyltransferase (DNMT) inhibitor 5-aza 2′-deoxycytidine (5AZADC) to treat the cells. Western blot analysis showed that STING expression was up-regulated in all cell lines after 5AZADC treatment, albeit to varying degrees.

In addition, DNMT1, DNMT3A and DNMT3B were significantly reduced after the cells were blown. Similarly, the use of siRNA to inhibit DNMT1 and DNMT3B also obtained similar results.

PNAS: The STING signal inside the tumor affects its tolerance to immunotherapy
(Figure 2, DNA demethylation treatment restores the expression level and signal activity of STING)

Further studies have shown that in STING-deficient melanoma cell lines, demethylation-mediated restoration of STING signal transduction can improve the expression and function of antigenic MHC class I molecules by up-regulating the expression of HLA, thereby enhancing They have the ability to recognize and kill cytotoxic T cells.

These findings not only clarify the role of epigenetic processes, especially the role of DNA methylation in the inherent STING signal transduction disorder of melanoma, but also highlight their role in tumor immune escape and T cell immunotherapy. Produces a function in tolerance.

 

 

(source:internet, reference only)


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