How to enhance the therapeutic efficiency of anti-PD-L1 cancer immunotherapy?

For most people, nothing is more terrible than cancer. Therapies such as chemotherapy and radiotherapy began to be used in the 1940s and late 1800s, respectively, while immunotherapy has only been used in recent years as a viable and successful treatment. Indeed, evading the host immune system is a basic feature of tumorigenesis, and it may be very important to elucidate how cancer cells do this, and how to promote the patient's own immune system to eliminate cancer cells, which may also be the basis for new immunotherapies.

Recently, in a study published in Nature Cell Biology, scientists from Tokyo Medical and Dental University and other institutions identified a special regulatory mechanism, that is, how PD-L1 immune checkpoint proteins affect the efficiency of anti-PD-L1 immunotherapy. Now we know that immunotherapy against immune checkpoint inhibitors can successfully treat certain cancer types, but only a small proportion of patients can have durable treatment outcomes, the researchers said.

PD-L1 expression is strictly controlled, and patients with tumors carrying increased PD-L1 expression levels respond well to Pd-L1 arrest. However, it remains unclear why increasing PD-L1 expression leads to increased sensitivity to PD-L1 arrest. Subsequently, the researchers analyzed one type of PD-L1 modification, acetylation modification, and found that removing this modification may promote PD-L1 to enter the nucleus and interact with DNA to regulate the immune response of the host body.

Using a variety of advanced molecular, biochemical, and bioinformatics analysis tools, the researchers analyzed the acetylation modification, localization characteristics, function, and interaction mechanism of PD-L1 and found that plasma membrane-localized PD-L1 could be transferred into the nucleus by interacting with transport pathway components. Specifically, by introducing a series of mutations in PD-L1 and expressing different acetyltransferases, the researchers found that PD-L1 could be acetylated by a special residue called Lys262 in the cytoplasm, using similar methods and protein removal mediated by short interfering RNAs, and the researchers also found that histone acetylase (HDAC) could specifically interact with PD-L1 and deacetylate it.

Protein modification including acetylation modification can affect protein stability, dimerization and localization. However, when investigators reduce the expression of HDAC2 protein in cells, they increase the level of acetylation, but they do not observe changes in protein stability or dimerization. The relevant study results show that acetylation modification and deacetylation of PD-L1 at specific residue sites play a key role in the nuclear transport process; in the nucleus, PD-L1 can regulate the expression of inflammatory and immune response-related genes, suggesting that PD-L1 can function to regulate the local tumor immune environment and thus control its sensitivity to immune checkpoint blockade therapy.

Finally, the researchers say, considering the health and economic burden of cancer populations worldwide, researchers need to conduct more in-depth studies to find new anti-cancer therapies, and the results of this study suggest that targeting the translocation of PD-L1 may help enhance the therapeutic efficiency of PD-1/PD-L1 block-based immunotherapy.

Collected by Creative BioMart

Creative BioMart presents immune checkpoint proteins developed as recombinant proteins. These products cover multiple species and are available in various expression hosts. Bio-activity of all immune checkpoint proteins has been assayed and confirmed, making them essential materials for mechanistic studies and development of new therapeutics.

Collected by Creative BioMart, a recombinant protein provider.