Sci Transl Med: Remove the "sugar coating" of tumor cells, and CAR-T becomes a "cannonball"!

T cells are activated by genetic engineering technology and equipped with a device that locates and navigates to the tumor - tumor chimeric antigen receptor ( Chimeric Antigen Receptor, CAR ), which can transform the ordinary " weapon " of T cells into a " super weapon " , namely for CAR-T cells .

T cells are activated by genetic engineering technology and equipped with a device that locates and navigates to the tumor - tumor chimeric antigen receptor ( Chimeric Antigen Receptor, CAR ), which can transform the ordinary " weapon " of T cells into a " super weapon " , namely For CAR-T CAR-T cells .

Glycosylation is one of the most common protein modifications, and the products come in the form of glycoproteins

January 19 , 2022 Researchers from Italy found extracellular expression of multiple tumors Researchers from Italy found that the abundance of extracellular N -N- glycan expression in multiple tumors correlated with glycan expression abundance with CAR-T The degree of CAR-T cell killing was negatively correlated.

Research results (Image source: STM )

Research results (Image source: STM )

To uncover the biological role of N- glycans in pancreatic cancer, the researchers first used a bioinformatics database to analyze mutations in the glycosyltransferases involved in the synthesis of these glycosyl groups and found that 19% of cBioportal 's 3,738 patients The samples carried genomic alterations in glycosyltransferases involved in N- glycan synthesis, and this feature was associated with poor prognosis .

To reveal the biological role of N- glycans in pancreatic cancer, the researchers first used a bioinformatics database to analyze mutations in glycosyltransferases involved in the synthesis of these glycosyl groups and found that among 3738 patients in the bioinformatics cBioportal , Nineteen percent of the samples carried genomic alterations in glycosyltransferases involved in N- glycan synthesis, and this feature was associated with poor prognosis .

Gene variants associated with N- glycan synthesis and prognosis in patients with pancreatic cancer (Credit: STM )

Gene variants associated with N- glycan synthesis and prognosis in patients with pancreatic cancer (Credit: STM )

After knocking out MGAT5 , it was found that the anti-tumor effect of CAR-T cells 44v6.

After knocking out MGAT5 , it was found that the anti-tumor effect of CAR-T cells 44v6.

Changes in tumor cells and CAR-T cells after knocking out MGAT5 (Source: STM ) 

Changes in tumor cells and CAR-T cells after knocking out MGAT5 (Source: STM ) 

To explore the basis for the enhanced antitumor efficacy of N- glycan-deficient tumor cells, the researchers analyzed the formation of immune synaptic IS , a limiting step in the targeting process of CAR-T cells .

To explore the basis for the enhanced antitumor efficacy of N- glycan-deficient tumor cells, the researchers analyzed the formation of immune synaptic IS , a limiting step in the targeting process of CAR-T cells .

Immune synapses and functional cytolysis after MGAT5 knockout (Image source: STM )

Immune synapses and functional cytolysis after MGAT5 knockout (Image source: STM )

Since the inhibition of N- glycans at the genetic level has shown good results, could pharmacological overcoming of tumor glycosylation achieve similar results? The researchers cleverly used the glucose / mannose analog 2DG to achieve this intervention

Since the inhibition of N- glycans at the genetic level has shown good results, could pharmacological overcoming of tumor glycosylation achieve similar results? The researchers cleverly used the glucose / mannose analog 2DG to achieve this intervention

The effect of pancreatic cancer on the sensitivity of 44v6.

The effect of pancreatic cancer on the sensitivity of 44v6.

We compared long-term combination therapy with 2DG and 44v6.

Comparison of 2DG treatment, 44v6.

Comparison of 2DG treatment, 44v6.
28 cell treatment in pancreatic cancer model ( Image credit: STM )

 In conclusion, the combination of CAR-T cells with 2DG showed good potential in the treatment of pancreatic cancer, and also achieved good results in the treatment of various other tumors, including tumors from the lung, ovary and bladder
.
Overall, this study found that extracellular N- glycans make tumors resistant to therapy by increasing the CAR-T cell activation threshold and promoting CAR-T cell exhaustion, and also provides new ideas for rational improvement of solid tumor treatment methods and methods.
direction
.

 In conclusion, the combination of CAR-T cells with 2DG showed good potential in the treatment of pancreatic cancer, and also achieved good results in the treatment of various other tumors, including tumors from the lung, ovary and bladder
.
Overall, this study found that extracellular N- glycans make tumors resistant to therapy by increasing the CAR-T cell activation threshold and promoting CAR-T cell exhaustion, and also provides new ideas for rational improvement of solid tumor treatment methods and methods.
direction
.

References:

References:

[1]Greco B, Malacarne V, De Girardi F, et al.
Disrupting N-glycan expression on tumor cells boosts chimeric antigen receptor T cell efficacy against solid malignancies.
Sci Transl Med.
2022;14(628):eabg3072.
doi: 10.
1126/scitranslmed.
abg3072.

[1]Greco B, Malacarne V, De Girardi F, et al.
Disrupting N-glycan expression on tumor cells boosts chimeric antigen receptor T cell efficacy against solid malignancies.
Sci Transl Med.
2022;14(628):eabg3072.
doi: 10.
1126/scitranslmed.
abg3072.


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