Peptide name : A11

Source/Organism : Annexin A1

Linear/Cyclic : Linear

Chirality : L

Peptide length: 11

C-terminal modification: Linear

N-terminal modification : Free

Non-natural peptide information:

Assay type : Biotin Pull Down assay

Assay time : 24-h

Activity : Not Available

Cell line : A-375

Cancer type : Skin Cancer

Other activity : Anticancer

Amino acid composition bar chart :

Molecular mass : 1225.3481 Dalton

Aliphatic index : 0.527

Instability index : 16.2636

Hydrophobicity (GRAVY) : -0.945

Isoelectric point : 8.5938

Charge (pH 7) : 0.8338

Aromaticity : 9.090

Molar extinction coefficient (cysteine, cystine): (0, 0)

Hydrophobic/hydrophilic ratio : 0.375

hydrophobic moment : -0.712

Missing amino acid : A,C,D,F,H,I,L,M,N,P,R,W

Most occurring amino acid : V

Most occurring amino acid frequency : 2

Least occurring amino acid : E

Least occurring amino acid frequency : 1

Secondary structure fraction (Helix, Turn, Sheet): (27., 27., 36.)

SMILES Notation: CC(C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CCC(=O)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)O)C(C)C)[C@@H](C)O

1 : Yu ZZ, et al. ANXA1-derived peptide for targeting PD-L1 degradation inhibits tumor immune evasion in multiple cancers. J Immunother Cancer. 2023; 11:(unknown pages). doi: 10.1136/jitc-2022-006345

Paper title : ANXA1-derived peptide for targeting PD-L1 degradation inhibits tumor immune evasion in multiple cancers.

Doi : https://doi.org/10.1136/jitc-2022-006345

Abstract : BACKGROUND: Immune checkpoint inhibitors (ICIs) therapy targeting programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) shows promising clinical benefits. However, the relatively low response rate highlights the need to develop an alternative strategy to target PD-1/PD-L1 immune checkpoint. Our study focuses on the role and mechanism of annexin A1 (ANXA1)-derived peptide A11 degrading PD-L1 and the effect of A11 on tumor immune evasion in multiple cancers. METHODS: Binding of A11 to PD-L1 was identified by biotin pull-down coupled with mass spectrometry analysis. USP7 as PD-L1's deubiquitinase was found by screening a human deubiquitinase cDNA library. The role and mechanism of A11 competing with USP7 to degrade PD-L1 were analyzed. The capability to enhance the T cell-mediated tumor cell killing activity and antitumor effect of A11 via suppressing tumor immune evasion were investigated. The synergistic antitumor effect of A11 and PD-L1 mAb (monoclonal antibody) via suppressing tumor immune evasion were also studied in mice. The expression and clinical significance of USP7 and PD-L1 in cancer tissues were evaluated by immunohistochemistry. RESULTS: A11 decreases PD-L1 protein stability and levels by ubiquitin proteasome pathway in breast cancer, lung cancer and melanoma cells. Mechanistically, A11 competes with PD-L1's deubiquitinase USP7 for binding PD-L1, and then degrades PD-L1 by inhibiting USP7-mediated PD-L1 deubiquitination. Functionally, A11 promotes T cell ability of killing cancer cells in vitro, inhibits tumor immune evasion in mice via increasing the population and activation of CD8+ T cells in tumor microenvironment, and A11 and PD-1 mAb possess synergistic antitumor effect in mice. Moreover, expression levels of both USP7 and PD-L1 are significantly higher in breast cancer, non-small cell lung cancer and skin melanoma tissues than those in their corresponding normal tissues and are positively correlated in cancer tissues, and both proteins for predicting efficacy of PD-1 mAb immunotherapy and patient prognosis are superior to individual protein. CONCLUSION: Our results reveal that A11 competes with USP7 to bind and degrade PD-L1 in cancer cells, A11 exhibits obvious antitumor effects and synergistic antitumor activity with PD-1 mAb via inhibiting tumor immune evasion and A11 can serve as an alternative strategy for ICIs therapy in multiple cancers.