PD-1 antibody "new partner" - HDAC2 inhibitor.

Immuno-checkpoint blocking therapy is an important advance in the field of cancer, and the representative drug PD-1/PD-L1 antibody has greatly improved the clinical outcomes of many human cancers.
, however, there are still some issues that need to be addressed with regard to cancer immunotherapy, including why only a small number of patients respond to PD-1/PD-L1 antibodies and why some patients do not have long-term treatment.
to find answers to these questions, scientists are gaining a deeper understanding of the mechanisms that regulate access to immune checkpoints.
PD-L1 is mainly defined as a PD-1 complex, which combines to inhibit the reaction of the effect T cells.
occur, PD-L1 is often expressed highly on tumor cells, forming an immune escape.
In addition to this function, which was originally discovered, PD-L1 has been reported as an anti-apoptosis molecule, as well as promoting the activation of the mammalian repamycin target protein (mTOR) and the metabolism of glycolysis in tumor cells.
in expression, PD-L1 appears to exist both in the cell membrane and in the cell.
interestingly, a 2019 study published in the journal Molecular Cell showed that PD-L1 in cells can also combine RNA transpedulated from DNA-damaged genes to increase the tolerance of tumor cells to DNA damage.
scientists believe that PD-L1 seems to have a new, unknown side.
, the regulatory mechanism that controls the positioning of PD-L1 subcellulars is not clear.
previous studies have confirmed that post-translation modification can regulate protein subcellular positioning.
although some researchers have observed acetylation of PD-L1 (a type of post-translation modification), the effect of this modification on the stability, function and positioning of PD-L1 is unclear.
: In a study published August 24 in the journal Nature Cell Biology, a team of scientists from Harvard Medical School reported on the mechanisms and new functions of PD-L1's subcellular positioning regulation.
specifically, they first demonstrated that PD-L1 was acetylized by p300 enzyme on its cytokine tail (C-tail), and that K263 was the only residual base of p300 acetylation at the end of PD-L1 cytones.
PD-L1 was primarily deacetylized by HDAC2 (Source: Nature Cell Biology), the researchers investigated which enzymes may have mediated PD-L1 deacetylization and found that pharmacological and genetic deficiencies in histogeneous deacetylase 2 (HDAC2) enhanced PD-L1 acetylation.
also confirmed that Lys 263 acetylation may have hindered the nuclear positioning of PD-L1.
compared with the acetylation of various parts, the acetylation of nuclear PD-L1 is relatively low.
addition, HDAC2 gene loss or pharmacological inhibition reduced PD-L1 levels in the nuclei, possibly due to an increase in Lys 263-bit acetylation of PD-L1.
these findings suggest that acetylation of Lys 263 on PD-L1 plays a key role in the nuclear positionation process.
An interesting finding is that compared to subsulteral primary tumors from B16F10 sources (PD-L1 is expressed primarily on cell membranes in primary tumors), pulmonary metastasis from B16F10 cells shows stronger nuclear PD-L1 expression, suggesting that the accumulation of nuclear PD-L1 may help tumor cells evade immune surveillance during metastasis.
study also found that membrane binding PD-L1 deacetylization through HDAC2 facilitates its interaction with a variety of proteins, including HIP1R.
PD-L1 interacts specifically with HIP1R through its cytostic tail.
Lys 263 acetylation may prevent this combination of PD-L1 and HIP1R.
hdAC2 inhibitor treatment also blocks the interaction between PD-L1 and HIP1R.
addition, in HIP1R knock cells, the nucleoPD-L1 is significantly reduced, suggesting that the protein may play an important role in the cell nucleation of PD-L1.
PD-L1 interacts with HIP1R and participates in the internal swallowing of mesh protein dependence (Source: Nature Cell Biology) Next, the study investigates the molecular mechanism of PD-L1's transfer from the mass membrane to the nuclei of the cell, and finds that HIP1R can be identified by the cargo joint protein (adaptin-beta2, AP2B1) to induce the internal swallowing effect of mesh protein media.
, PD-L1 binds to the intermediate silk protein Vimentin (the middle wire is one of the cytostebrae), allowing it to enter the nucleocle through the cytostebrae.
vimentin deficiency reduces the expression of PD-L1 in the nucleation of the cell.
relies on deacetylized PD-L1 nuclear migration to support tumor immune escape . . . membrane binding PD-L1 deacetylization through HDAC2 facilitates its interaction with a variety of proteins, including HIP1R, and allows PD-L1 to be swallowed internally.
PD-L1 is further transported through the cytostebrae to the nucleation by binding to Vimentin.
, the protein is entered to mediat the nuclear transposition of PD-L1, which then interacts with DNA to control gene transcription.
On the one hand, nuclear PD-L1 appears to regulate the expression of antigen-related genes (e.g. MHC-I-related genes) and inflammation-promoting pathway-related genes (e.g. IFN-I-related genes) to improve the identification of tumor cells by cytotoxic T lymphocytes (CTLs).
, on the other hand, nuclear PD-L1 also increases the expression of other immune checkpoint genes, including PD-L2 and VISTA, which in turn increases the depletion of cytotoxic T lymphocytes and impairs the therapeutic effect of PD-L1 blocking.
although further research is needed, nuclear PD-L1 activity also appears to be associated with the invasiveness of tumor cells.
(Source: Nature Cell Biology) RNA sequencing and chromatin immunosequencing combined with ultra-high-volume DNA sequencing analysis showed that nuclear PD-L1 binds to DNA as a regulatory factor for gene transcription.
further finding that this nuclear activity of PD-L1 may promote immune escape from tumors.
, nuclear PD-L1 triggers the expression of other immune checkpoint molecules, leading to possible access to immunotherapy resistance.
And blocking the nuclear transposing of PD-L1 with HDAC2 inhibitors may reduce transcription of these immuno-checkpoint genes, resulting in increased CD8-cytotoxic T-cell immersion in tumors and lower TNF alpha levels, which in turn enhances the anti-tumor immune response triggered by PD-1 antibodies.
in the MC38 tumor model with gene mice, hdAC2 inhibitors combined with PD-1 antibodies significantly slowed tumor growth and improved survival rates compared to the PD-1 antibody treatment group (figure e, f below).
Nred nuclear PD-L1 regulates immune response and regulates gene expression of path path pathrapies to influence the efficacy of anti-PD-1 immunotherapy (Source: Nature Cell Biology) Although this new study reveals previously undetected functions of PD-L1 and relies on acetylation's nuclear positioning regulatory mechanisms, it raises interesting questions.
For example, the study reported that nuclear PD-L1 also has the ability to raise the genes of other immune checkpoints (including PD-L2, VISTA) in tumor cells, which helps tumor cells develop resistance to PD1/PD-L1 blocking therapy.
, however, nuclear PD-L1 appears to strongly induce immune response-related genes, including type I and type II interferon signaling path, NF-kB signaling path, and antigen delivery path.
findings suggest that nuclear PD-L1 may increase the inflammatory response of tumor microenvironments, promote the delivery of new antigens, but also promote anti-tumor immune escape.
exactly what determines the PD-L1 stimulation of one path, not another, remains to be seen.
possible explanation is that tumor cells expose themselves to cytotoxic T cells and are identified, just to better drive them toward depletion.
summary, this new study reveals previously unknown mechanisms for the positioning and regulation of Acetylated PD-L1 nuclear location, technology that provides a deeper understanding of the PD-L1 path.
at the same time, the paper shows that PD-L1's interesting role as a transcription regulator and its new function of gene regulation in inflammatory pathfage and immuno-checkpoint may be important for the use of checkpoint blocking therapy and HDAC inhibitors.
, more research is needed to better understand the mechanisms that regulate the activity of nuclear PD-L1 and its relationship to tumor invasiveness.
resources: s1. Xinyi Tu et al. PD-L1 (B7-H1) Competes with the RNA Exosome to Regulate the DNA Damage Response and Can Be Targeted to Sensitize to Radiation or Chemical. Molecular Cell (2019). Yang Gao et al. Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy. Nature Cell Biology (2020). The Hidden side of PD-L1 (Source: Nature Cell Biology)