Sub-Journal of "Cell": Cancer cells, you are here again!

Immune checkpoint therapy is undoubtedly a hot direction in the field of tumor treatment in the near future.
A series of monoclonal antibody drugs led by PD-1 antibodies have been put into use and have achieved surprising results.

However, in actual clinical applications, only about 2-3% of patients can benefit from immunotherapy.

Resistance to immunotherapy may be caused by many reasons, for example, mutations in tumor cells themselves cause the drug to lose its target, and the anti-inflammatory ability of immune cells is inhibited, and so on.

Cunning cancer cells can create an anti-inflammatory microenvironment by using some signal pathway changes in their own cells to avoid the killing of immune cells.

For example, previous studies have found that, to some extent, the sugar in the tumor microenvironment is competitively taken up by cancer cells and immune cells.
Therefore, once the uptake of one party increases, the uptake of the other party decreases, and proliferation and function may be affected.
Inhibit [1].

A recent study published in the journal Cell Metabolism has discovered a new mechanism by which cancer cells make T cells undereating [2].

The FTO protein in cancer cells can enhance the expression of glycolysis-related genes in cancer cells and inhibit the function of infiltrating CD8+ T cells in the tumor microenvironment.

The use of FTO inhibitor Dac51 can enhance the function of CD8+ T cells, and the combination of PD-L1 antibody can help to clear the tumor.

Previous studies have found that cancer cells may inhibit the infiltration and killing of immune cells through apparent remodeling, such as adjusting histone modification, DNA methylation, chromosome structure, etc.
to regulate immune cell antigen presentation and cytokine secretion.

In their early work, researchers discovered an important relationship between reversible RNA methylation modification and cancer development and metastasis [2].

Therefore, they speculated that this methylation modification may also be one of the reasons for the immunosuppressiveness of the tumor environment.

Researchers first searched for genes related to CD8+ T cell function activation based on the map of cancer big data, including positive correlations and negative correlations.

Among them, FTO shows a high reverse correlation with T cell function, and has similar results in a variety of tumors.

FTO is a m6A demethylase, which is related to epigenetic modification.

The genes related to the activation of CD8+ T cell function were screened.
Therefore, the researchers tested the FTO knockdown in two cancer cell lines B16 and LCC.
Surprisingly, when the FTO knockdown cancer cells were When the mice were injected subcutaneously, it was found that the tumor tissue in the control group grew faster than the tumor tissue knocked out by FTO.

When they repeated the experiment with mice with birth defects in T/B cells, they found that this difference disappeared, indicating that this change was brought about by adaptive immune cells (ie, T/B cells).

The researchers also isolated tumor tissues in FTO knockdown mice, and found that the number of CD8+ T cells was almost doubled; and they secreted cytokines IFN-γ and granzyme that resist cancer cells.
The level of B has also increased.

Knockdown of FTO in cancer cells leads to stronger CD8+T infiltration and function, and tumor formation is blocked.
Glycogen is very important for the rapid growth and invasion of cancer cells, and there are also previous reports in the literature about the high-speed glycogen utilization of this cancer cell.
It inhibits the metabolism of T cells and directly affects their functions [3].

Therefore, the researchers speculated that FTO knockdown may be related to changes in the ability of glycogen utilization—glycolysis.

Sure enough, the researchers observed that the expression of genes related to glycolysis pathways in FTO knockdown cancer cells was reduced, and this reduction can be eliminated by overexpression of key proteins and the use of drugs to activate glycolytic enzymes.

Since FTO itself is a m6A demethylase, the experimenters tested the m6A methylation level in cancer cells before and after FTO knockdown, and found that the overall m6A methylation level increased after knockdown, especially in Near the terminator; and some genes have decreased expression levels, including Jun and Cebpb, which are enzymes related to glycolysis.

When the researchers tried to improve the modification efficiency of FTO, they found that the expression of JunB and CEBPβ ​​increased, indicating that FTO does act directly on the mRNA of glycolysis-related enzymes to regulate its expression; while in the cell-level experiments, the effect of FTO increased The cancer cells also reduced the ability of co-cultured CD8+ T cells to secrete anti-cancer factors.

When the efficiency of FTO modification increases, the expression of glycolysis-related enzymes increases, and CD8+T function is inhibited.
Researchers finally used a FTO inhibitor Dac51 found in previous work, which can efficiently and stably bind to FTO and inhibit it.
Its m6A regulatory function.

FTO inhibitor: The action of the small molecule drug Dac51Dac51 leads to a decrease in the level of glycolysis of cancer cells, an increase in T cell infiltration, and an increase in tumor killing ability, but this is not caused by the toxicity of the drug.

In human tumor tissues and tumor-bearing mice, the addition of Dac51 resulted in decreased expression of glycolysis-related enzymes in cancer cells, continuous activation of T cells and high cytokine expression.

When the PD-L1 antibody and Dac51 are used on mice that grow tumors at the same time, the growth rate of mouse tumors is significantly reduced, and the survival rate is greatly improved.

The surviving mice were inoculated twice with higher doses of tumor cells, and it was found that the mice could still clear the cancer cells well, indicating that these cytotoxic T cells have memory.

The combination of Dac51 and PD-L1 antibody reduces tumor formation and enhances the survival rate of mice.
In general, this paper has discovered a new mechanism for cancer cells to regulate the microenvironment and escape immune surveillance.

Through FTO epigenetic modification, cancer cells can enhance glycolysis, and may grab energy in this way, making T cells "not full", thereby weakening their anti-tumor function.

Fortunately, Dac51 can efficiently and stably bind FTO, inhibit the carbohydrate metabolism of cancer cells, thereby indirectly increasing the function of cytotoxic T cells.

This may be able to contribute to the formation of immunotherapy.

References: 1.
Reinfeld BI, Madden MZ, Wolf MM, Chytil A, Bader JE, Patterson AR, et al.
Cell-programmed nutrient partitioning in the tumour microenvironment.
Nature 2021.
2.
-metabolism/fulltext/S1550-4131(21)00167-43.
Han D, Liu J, Chen C, Dong L, Liu Y, Chang R, et al.
Anti-tumour immunity controlled through mRNA m(6)A methylation and YTHDF1 in dendritic cells.
Nature 2019; 566(7743):270-274.
4.
Cascone T, McKenzie JA, Mbofung RM, Punt S, Wang Z, Xu C, et al.
Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy.
Cell Metab 2018; 27(5):977-987 e974.
The author of this article | Dai Ling Chief Editor | Dai Siyu