Harvard Medical School Demonstrated that Ketogenic Diets Increase the Anticancer Effect by Reducing pD-L1 Abundance
The unusal energy condition may cause many kinds of metabolic disease, including obesity, diabetes and even cancer, which underlining mechanisms is hard to be clear.
Wei wenyi professor’s team in Harvard Medical School demonstrated that the changes of energy condition lead by ketogenic-diet can strengthen the effect of anti CTLA-4 immunization therapy through decreasing the PD-L1 protein level and adding the expresstion of type I interferon (IFN) and antigen presenting gene.
Programmed cell death receptor(PD-1) is an important kind of immunosuppressive molecule, which can downregulate the immune response to prevent autoimmune diseases.Pd-l1 on the surface of tumor cells binds to PD-1 on T cells to promote the immune escape of tumor cells.
Therefore, by blocking the binding of PD-L1 to PD-1 with inhibitors or reducing the pD-L1 on the surface of tumor cells, the killing effect of T cells on tumor cells can be restored.
First, the team found that energy stress or a ketogenic diet reduced the expression abundance of PD-L1 protein and ketogenic diet can enhances the anticarcinogenic effect of ctLA-4 immune checkpoint blockade.
Further studies have shown that energy deprivation activates AMPK kinase and phosphorylates serine at position 283 of PD-L1, disrupting the interaction between PD-L1 and CMTM4 and subsequently triggering PD-L1 degradation.
In addition, AMPK phosphorylates EZH2, thereby disrupting PRC2 function and enhancing the expression of type I interferon (IFN) and antigen-presenting genes.
By these mechanisms, AMPK agonists or ketogenic diets can enhance the efficacy of anti-CTLA-4 immunotherapy and improve overall survival in tumor mouse models.
In summary, It demonstrated that energy status determines the abundance of PD-L1 and the anti-tumor effect of immune checkpoint therapy, further revealing the key role of AMPK in regulating the anti-tumor effect of immune checkpoint therapy. Energy deprivation activates AMPK and phosphorylates SER283 of PD-L1.Thus, the interaction between PD-L1 and CMTM4 is destroyed and pD-L1 degradation is subsequently triggered.
The study also adds to evidence that AMPK agonists or ketogenic diets are more effective against cancer when combined with CTLA4 immune checkpoint therapy.
Now Wuxi Donglin Sci and Tech Development has developed a variety of ELISA kits for type I interferon .
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