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Wen-Man PD-1 (CD279) is an inhibitory body in active T cells, which maintains extrinsic immunity by combining with ligations PD-L1 and PD-L2, and also plays a role in impairing anti-tumor immunity.
-targeted PD-1 or its matching blocking antibodies have revolutionized cancer immunotherapy, but only a small percentage of patients are currently able to produce a lasting anti-tumor response, with most patients responding only briefly or completely unresponsively.
years, the clinical development around the PD-1 path seems to have entered a bottleneck period, and various joint treatments have not made a substantial breakthrough.
, scientists have recently begun an in-depth study of the mechanisms by which PD-1 paths transmit inhibitory signals, hoping to find key targets that could improve treatment.
: In a recent review of "Revisiting the PD-1 Pathway" published September 18 in the journal Science Advances, four scientists from Harvard Medical School outlined the latest advances in the mechanisms of the PD-1 pathway and discussed the implications of these new discoveries and the gaps to be filled.
, PD-1 and its mating bodies are expressed in a variety of cells in the congenital immune and adaptive immune system, and their expression patterns have been widely studied.
, scientists focused primarily on transcription mechanisms that induce PD-1 and its liant expression, but recent studies have found that expressions of PD-1 and PD-L1 are also regulated by post-translation modification (Figure 1).
CRISPR-based screening revealed that the algal glycosyl metastase Fut8 regulates the expression of PD-1 on the cell surface (Figure 1A), and that T cells treated with algal glycosylation inhibitors showed stronger anti-tumor effects in the body.
, however, the precise bio-chemical mechanism of algal glycosylation affecting the structure and function of PD-1 has yet to be clarified.
expression of
PD-1 may also be regulated by the E3 connective enzyme FBXO38, which mediates K48-connected polypropulation (K48-linked polybiquitination) at PD-1K233 bits and subsequent protease degradation (Figure 1B).
figure 1 . . . post-translation modification regulation PD-1 expression . . . A. In the endodermal mesh (ER), PD-1 underlying at N49 and N74 residues, which in turn underlying algal glycosylation in the gould, causes PD-1 to continue to express and transmit inhibitory signals on the cell membrane.
genetic loss or pharmacological inhibition of fut8, a glycosyl transferase, can reduce the glycosylation, expression and inhibitory signals of PD-1 algae, resulting in increased T-cell activity.
B. FBXO38 Ubiganic connective enzyme mediates PD-1 Ubiganization at K233 bits, resulting in PD-1 internalization and protease degradation.
gene knock-down or reduction of FBXO38 can lead to an increase in PD-1 expression, thereby enhancing inhibitory signaling paths and T-cell suppression.
expression of C. PD-L1 in tumor cells can be stabilized by glycosylation.
GSK3 beta can antagonize this mechanism by binding to the non-glycosylated form of PD-L1, resulting in T180 and S184 bit phosphate, as well as β-TrCP-mediated PD-L1 ubiquitinization and protease degradation.
EGFR-mediated signal can inhibit phosphorylation and degradation of GSK3 beta-mediated PD-L1, promoting PD-L1 stability and immunosuppression.
antibodies (anti-gPD-L1) targeting glycosylated PD-L1 can block interaction with PD-1 and induce the internalization and degradation of PD-L1.
D. In cancer cells, TNFR (TNF receptor)-mediated signals cause IKK beta-mediated p65 activation and nuclear translocation, which in turn leads to CSN5 transcription, which enhances immunosuppressive activity by directly de-urination or inhibition of PD-L1 ubiturization.
CMTM4/6 interacts with PD-L1 on the cell surface, reducing its ubimation and increasing the half-life of the PD-L1 protein.
and stability of PD-L1 (Source: Science Advances) PD-L1 can also be regulated at translated levels through glycosylation and ubiquitinization.
only non-sugar-based PD-L1 has been found to interact with GSK3 beta, leading to PD-L1 phosphate-dependent protease degradation (Figure 1C).
contrast, by directly de-urination or inhibiting ubibinization and degradation of PD-L1, CSN5 (COP9 signalosome 5) is required for TNF-α-mediated PD-L1 stabilization (Figure 1D).
2, PD-1 and its mating body interaction Figure 2 . The interaction pattern between PD-1 and PD-L1 (Source: Science Advances) As shown in Figure 2A, PD-L1 expressed on antigen-delivered cells (APCs) or tumor cells is expressed in reverse binding to PD-1 trans-binding expressed on T cells, weakening the activation of T-cells mediated by the interaction between TCR/MHC and CD28/B7-1.
PD-1 or PD-L1 blockable antibodies can reduce T-cell suppression by blocking the reverse interaction of PD-1/PD-L1.
As shown in Figure 2B, when PD-1 and PD-L1 are expressed together on APCs or tumor cells, PD-1 binds to PD-L1, reducing the ability of PD-L1 to bind to PD-1 transsyse expressed on T cells.
As shown in Figure 2C, the smooth interaction of PD-L1/B7-1 on APCs or tumor cells can also disrupt the reverse binding of PD-1/PD-L1, resulting in a decrease in PD-1-mediated T-cell inhibition.
addition, the smooth combination of PD-L1/B7-1 did not destroy the combination of B7-1 and CD28, and the co-stimulation effect of B7-1/CD28 interaction remains.
, the smooth combination of PD-L1/B7-1 disrupts the B7-1/CTLA-4 axis.
As shown in Figure 2D, the addition of blocking anti-PD-L1 antibodies to block PD-1/PD-L1 interactions also blocks PD-L1/B7-1 interactions, binding the released B7-1 with CTLA-4 and transmitting an inhibition signal.
this case, blockable anti-CTLA-4 antibodies may benefit by blocking CTLA-4-mediated T-cell suppression.
as shown in Figure 2E, the smooth interaction of PD-L1/B7-1 on APCs prevents the reverse swallowing of regulated T-cells (Treg) CTLA-4-mediated B7-1, which causes the APC surface B7-1 to be missing.
As shown in Figure 2F, anti-PD-L1 antibodies can bind B7-1 to CTLA-4 on Tregs by interfering with PD-L1/B7-1 interactions, promoting CTL-4-mediated B7-1 trans-swallowing and weakening the co-stimulation of B7-1 mediated, thus negatively affecting immunotherapy.
III, PD-1 signal conduction mechanism and target 1, PD-1/SHP-2 interaction PD-1 and its notation are members of the B7/CD28/CTLA-4 family, which is a type I transglobulin, sharing a model infrastructure consisting of 1 "IgV extracellary domain", 1 "trans-membrane domain" and 1 "cytosteral tail region".
although the extracellal structure and interaction of PD-1 have been widely studied, there is very little information about its in-cell structure and signal transduction mechanism.
PD-1's cytoplasm tail region contains two tyrosine-based structural substates: ITIM (immunoreceptor tyrosine-resedory motif) and ITSM (immunoreceptor tyrosine-basemotif).
study has shown that PD-1 inhibitory function relies on ITSM phosphorylation tyrosine, which prioritizes the recruitment of phosphatase SHP-2 (Src homology region 2 domain-containing phosphatase-2).
although it is generally accepted that SHP-2 is a key medium for PD-1 inhibitory function, the exact mechanism by which PD-1 is involved in the activity of SHP-2 enzymes remains unclear.
3 summarizes the interaction between PD-1 and SHP-2, and as shown in Figure A, according to the two-step binding model, SHP-2 C-SH2 can be used with PD-1 pY-ITSM with a strong pro Combined with force, recruit PD-1 to SHP-2, while PD-1pY-ITIM binds to N-SH2 to replace N-SH2 from the PTP bit point to activate phosphatase.
As shown in Figure B, according to the d?poly model, SHP-2 binds to two pY-ITSM residues on two PD-1 molecules through its N-SH2 and C-SH2 domains, thus forming a PD-1:PD-1 diogenes and inducing the activation of SHP-2.
Figure 3 . Multiple studies of PD-1/SHP-2 interaction patterns (Source: Science Advances) 2, PD-1 Targeted Signal Paths Have investigated the effects of PD-1 on key signal path paths activated by TCR and co-stimulation subjects to determine how PD-1 inhibits amplification and differentiation of activated T cells, and how to inhibit the production of cytokines.
There has been a debate about which signal path is the main target of PD-1, most studies support PD-1 mainly target TCR and TCR downstream signal cascading, but there are also studies showing that the co-stimulation of the subject CD28 is the main target of PD-1, and other studies have shown that TCR and CD28 are targeted equally by PD-1.
, however, while the issue is controversial, there is a consensus among many scientists that SHP-2 is the only direct partner currently identified to regulate PD-1 inhibitory signals in normal T cells.
, however, it has since been found that when SHP-2 is missing, SHP-1 phosphatase can replace SHP-2 and compensate for the inhibitory function of PD-1.
In addition, it is worth mentioning that although PD-1-mediated signaling and functional effects mainly act on T cells, there are studies suggesting that the PD-1:PD-L1 pathrapy may also transmit signals in cancer cells.
study found that cancer cells may use the PD-1:PD-L1 path path line to trigger mTOR signals in adjacent tumor cells to support their growth.
, the mechanism of PD-L1 signaling and the expression of PD-L1 in cancer cells were initially thought to be the main mechanisms of cancer-mediated T-cell immunosuppression and depletion.
, a growing body of research has shown that expression in antigen-presented myelin cells in tumor microenvironments is equally important for mediated immunosuppressive properties of tumor-specific T cells.
the dedes and macrophages that express PD-L1 may play a leading role in mediated T-cell immunosuppression, and the expression of PD-L1 in tumor microenvirons presented in myelin cells can predict the efficacy and therapeutic outcomes of PD-L1/PD-1 blocking.
PD-L1 can also be expressed in active T cells, but its ability to transmit signals to T cells remains controversial.
signal conduction mediated by PD-L1 was first studied in cancer cells.
PD-L1 is considered an immune barrier that transmits anti-apoptosis signals in cancer cells after being connected to PD-1 expressed on T cells, inducing tolerance to T-cell-mediated killing and protecting cancer cells.
studies have shown that PD-L1 can also activate the in viscemic signaling of cancer cells in a way that does not rely on PD-1, and enhance cancer cell proliferation and survival by inhibiting autophagy and activating mTOR.
the PD-L1 cytokine tail region has not been identified as a distinct sequence associated with signal conduction, indicating that PD-L1 uses an unconventional signal conduction base sequence.
recently, researchers found three conservative sequences in the cytoset tail region of PD-L1, namely ,RMLDVEKC, DTSSK, and QFEET.
note that lysine 271 and 280 in the RMLDVEKC and DTSSK subsequents are considered targets for ubiquitinization, leading to instability and downgrading of PD-L1.
PD-L1 may also reduce ifN-mediated cytotoxicity by relying on STAT3/caspase-7 to transmit inhibitory signals to tumor cells.
and conservative RMLDVEKC subsector is needed to reduce IFN toxicity, the DTSSK base sequence plays the role of PD-L1 functional negative regulatory factor.
inhibition of PD-L1 expression or treatment with PD-1 antibodies is expected to make cancer cells sensitive to IFN cytotoxicity (Figure 4).
figure 4. PD-L1 protects tumor cells from IFN-mediated cytotoxicity by signaling (Source: Science Advances) V, PD-1 Determines the differentiation and function of T cells by regulating metabolic reprogramming, which not only supports growth and proliferation, but also play a key role in driving differentiation.
phosphate oxide is the main energy source for naïve T cells, but when activated, naïve T cells undergo metabolic reprogramming to perform aerobic glycolysis (also known as the Warburg effect), while increasing glutamine intake and decomposition metabolism to maintain the health of the effect T cells and drive the differentiation of memory T cells.
PD-1 signaling alters metabolic reprogramming and contributes to the use of fatty acids in β-oxidation, thereby impairing glycolysis, glutamine decomposition, and the metabolism of branched chain amino acids.
and glycolysis can block the differentiation of TH17 cells and promote the development of Tregs.
, oxidation paths may be a metabolic checkpoint that is expected to be used to enhance PD.