4.1.3 The Mechanism of PD-1/PD-Ls Signaling
PD-1 ligation, along with B-cell receptor (BCR) signaling, results in phosphorylation of the cytoplasmic domain tyrosine and recruitment of Src homology phosphatase 2 (SHP-2).Then SHP-2 dephosphorylates BCR-proximal signaling molecules including Igα/β and Syk, which attenuates the activation of downstream molecules including PLCγ2, PI3K, vav, and ERK1/2.PD-1 inhibits T-cell receptor (TCR) signaling by similar mechanisms.PD-1 ligation, along with TCR signaling, results in phosphorylation of the cytoplasmic domain tyrosine and recruitment of SHP-2 to the C-terminal tyrosine in the immunoreceptor tyrosine-based switch motif (ITSM).Then SHP-2 dephosphorylates TCR-associated CD-3ζ and ZAP70, resulting in inhibition of downstream signaling.Furthermore,blockade of PI3K activation, followed by the blockade of cell survival gene Bcl-XL, decreases interleukin-2 (IL-2) production and glucose metabolism.Down regulation of IL-2 makes further efforts to induce CD8+T and CD4+T cell anergy.Interestingly, it is reported that phosphorylated ITSM can recruit SHP-1 in addition to SHP-2.However, the contribution of SHP-1 to the inhibitory function of PD-1 can be much less compared to that of SHP-2 [4].
Immune checkpoint blockers (ICB) act on T-cell immunosuppressive targets such as Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), PD-1, or block immunocheckpoint-related ligands such as PD-L1, bringing hope to patients with refractory tumors, as an important means of tumor immunotherapy, it can significantly improve the prognosis of tumor patients.Studies have shown that after the interaction between PD-L1 and PD-1, phosphorylation of the immunoreceptor tyrosinebased inhibitory motif (ITIM) and ITSM of the latter can be induced.Subsequently, protein tyrosine phosphatase SHP-2 is recruited to weaken the activation signal of T cells and mediate immune escape.The application of ICB can block the recruitment of SHP-2, lose the phosphatase dephosphorylation, and then activate T cells to play the immune function, as shown in Figure 4.1.
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Figure 4.1 Molecular mechanism of PD-1/PD-L1 blocker action.After PD-1/PD-L1 conjugation, the ITIM and ITSM structures in the PD-1 cell membrane region were phosphorylated, and phosphatase SHP-2 was recruited to the cell membrane region, so that the TCR and CD28 membrane domains were dephosphorylated, and the first signal and co-stimulation signals of T cells were activated, which could not be transmitted to the downstream proteins, and the T cells could not be activated.When PD-1 /PD-L1 monoclonal antibody is activated, the intramembrane motif of PD-1 cannot be phosphorylated,and SHP-2 recruitment is lost.There is no phosphatase dephosphorylation, and the activation signals of TCR and CD28 can be transmitted to the downstream proteins, finally stimulating the proliferation and differentiation of T cells.(Please scan the QR code on the Preface to get original color figures.)
Source: Wang Z, Wu X.“Study and Analysis of Antitumor Resistance Mechanism of PD1/PD-L1 Immune Checkpoint Blocker”.CancerMedicine, 2020, DOI:10.1002/cam4.3410
Moreover, PD-L1 alone can induce the conversion of naive CD4+T cells into Foxp3+ induced T reg(iTreg) cells, which are the key mediators of peripheral tolerance that actively suppress effector T cells.In addition, PD-L1 can mediate an inhibitory signal by ligating B7-1.Aside from the inhibitory effect, PD-L1 and PD-L2 can also provide positive signal to T cells independent of PD-1,as mutants of PD-Ls with abolished PD-1 binding capacity can still stimulate proliferation and cytokine production of T cells from normal and PD-1-deficient mice.It suggests that there is another unknown receptor for PD-1 and PD-L2 [5].