Nat Cell Biol: Is it cancer-promoting or anti-cancer? PD-L1 has an unknown side.

The rise of cancer immunotherapy has brought a new dawn to the complete fight against cancer, the "king of all diseases".
, epidemic checkpoint blocking therapy has become one of the most popular immunotherapy therapies today, which has significantly changed the current pattern of cancer treatment, and PD-1/PD-L1 immuno-blocking therapy is the most typical representative.
pathogenic cell death complex (PD-1), an important immunosuppressive molecule that lowers the immune system's response to avoid autoimmune diseases.
PD-L1 on the surface of tumor cells with PD-1 on T cells, prompting tumor cells to gain immune escape.
, inhibitors inhibit the binding between the two, allowing T-cells to kill and remove tumor cells.
PD-1/PD-L1 immunosuppressor therapy, PD-L1 has long been widely described as a membrane binding complex for PD-1.
but surprisingly, a new study has found a new, little-known role in PD-L1, which binds DNA to control different pathways associated with avoiding immune surveillance or tumor micro-environmental inflammation.
the study, published in the journal Nature Cell Biology, was conducted by Harvard Medical School, the First Affiliated Hospital of Xi'an Jiao university in China, and the Tokyo Medical Dental University in Japan.
immune checkpoint blocking therapy has greatly improved the clinical prognostion of many human cancers, but it has to be said that the immune system is sophisticated and complex, and human understanding of it is still very poor.
a deeper understanding of the regulatory mechanisms of the immune checkpoint path path, will help us address legacy issues such as the low response rate and lack of long-term therapeutic effects observed in patients.
In the context of cancer, PD-L1 is usually expressed highly on tumor cells to evade immune surveillance, but there are also reports that high expression of PD-L1 can make tumor cells more sensitive to PD-1/PD-L1 inhibitors.
addition, studies have found that in human colorectal and prostate cancers, the expression of cellular nuclear PD-L1 is associated with poor prognostication.
these studies suggest that the functions of PD-L1 may be complex and diverse, rather than the membrane bindings previously thought to be simply PD-1.
study, which involved acetylation at the end tail of PD-L1 C, the team discovered new functional and regulatory mechanisms for PD-L1.
specifically, they demonstrated that PD-L1 was acetylized by p300 enzymes on the tail of its C end (cytosyl side), while other acetyl transferases did not promote acetylation of PD-L1, and that acetylation disappeared when the tail of the end of PD-L1 C was missing.
, by mutations in five lysine residues at the end of PD-L1 C, the researchers determined that K263 was the only residual base on the tail of PD-L1 C that was p300 acetylized.
Yang Gao and others further studied which enzymes might mediate PD-L1 deacetylization, and they found that pharmacological and genetic deficiencies in hismoglobin deacetylase 2 (HDAC2) enhanced Acetylation of PD-L1.
map of the end tail domain and amino acid residues of PD-L1 C, the researchers also detected PD-L1 in the nucleus and cytostebrae of cancer cell lineages in humans and mice.
they found that when PD-L1 C end tails are missing and HDAC2 is treated, the distribution of PD-L1 in the nucleus decreases, suggesting that deacetylization of PD-L1 may have prevented it from being positioned toward the nucleus.
these findings, the team shifted its focus to exploring the molecular mechanisms of PD-L1 nuclear shift.
, mass spectrometry identified a variety of PD-L1 interaction molecules, including endodontic and nuclear transport proteins, as well as Huntington's interaction protein 1-related proteins (HIP1R).
researchers noted that PD-L1 acetylation reduced the interaction between HIP1R and PD-L1, and that nuclear PD-L1 decreased significantly in HIP1R knock-out cells, suggesting that the protein may play an important role in the transfer of PD-L1 to the nuclei.
the deacetylization-dependent PD-L1 nuclear transposition promotes tumor immune escape In fact, the team found that HIP1R can be identified by cargo joint proteins, thereby inducing mesh protein-mediated internal swallowing, PD-L1 and intermediate silk protein Vimentin identification, which can be transported through the cell skeleton to the nuclei of the cell, and then nuclear transport protein (importins) to mediate its nuclear transposition.
RNA-seq and ChIP-seq analysis of PD-L1 in the nuclei of cells showed that PD-L1 in the nuclei of cells can bind to DNA and act as a regulatory factor for gene transcription.
RNA-seq analysis, the researchers found a greater overlap between the PD-L1 ChIP-seq peak gene and the differential expression gene in PD-L1 knock-out cells.
PD-L1 knock-down gene in cells has PD-L1 reoclusion peaks, and a variety of transcription factors have a new PD-L1-specific binding base sequence.
results support that the expression of PD-L1-dependent genes is mediated by the interaction of PD-L1 with DNA or transcription factors binding to DNA.
acetylation of PD-L1 is inhibited by genetic or pharmacological methods, which prevents its nuclear susception and promotes the reprogramming of immune genes.
this, the researchers combined anti-PD-1/PD-L1 therapy with HDAC2 inhibitors to inhibit PD-L1 nuclear susception and to successfully treat results in mouse tumor models.
same time, the study also reported that nuclear PD-L1 was able to raise immune checkpoint genes such as PD-L2 and VISTA in tumor cells, thereby promoting resistance of tumor cells to PD1/PD-L1 blocking therapy.
addition, nuclear PD-L1 appears to strongly induce immune response-related genes, including I. and II interferon signaling pathlines, NF-kB signaling paths, and antigen delivery paths.
results suggest that nuclear PD-L1 may increase the inflammatory response of tumor microenvironments, promote the delivery of new antigens, and also promote anti-tumor immune escape.
pattern map shows how nuclear PD-L1 enhances the immunotherapy response by affecting the expression of immune-related genes In short, nuclear PD-L1 has a complex dual effect, which can not only promote tumor occurrence, but also inhibit tumor immune escape.
this dual effect raises the question of the mechanism by which nuclear PD-L1 controls its transcriptional regulatory activity.
, in fact, what determines PD-L1 stimulating one path rather than another remains to be seen.
conclusion, the study sheds light on the acetylation dependence regulation of PD-L1 nuclear positioning, which gives people a better understanding of the PD-L1 approach.
interestingly, the researchers also revealed the dual effects of nuclear PD-L1 on tumors, and their involvement in inflammatory pathfage and immune checkpoint gene control may have important guiding effects on the use of immuno-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, it has to be said that this study is an important part of solving the puzzle.
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