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. 2022 Sep;12(9):e1019.
doi: 10.1002/ctm2.1019.

Chrysin targets myeloid-derived suppressor cells and enhances tumour response to anti-PD-1 immunotherapy

Yinan Li  1 , Ru Yang  1 , Xiu Huang  1 , Caihong Chen  1 , Daolei Dou  1 , Qianqian Wang  1 , Xinying Wu  1 , Huijuan Liu  1 , Tao Sun  1
Affiliations

Chrysin targets myeloid-derived suppressor cells and enhances tumour response to anti-PD-1 immunotherapy

Yinan Li et al. Clin Transl Med. 2022 Sep.
No abstract available

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

FIGURE 1
FIGURE 1
Chrysin (Chr) inhibits the accumulation and function of myeloid‐derived suppressor cells (MDSCs) in vitro: (A) CCK8 assay results of Chr on MDSCs; (B) effect of Chr on B16‐F10‐bearing C57BL6 mouse myeloid cells, as detected by flow cytometric analysis; (C) analysis of MDSCs apoptosis induced by Chr using Annexin V/PI assay; (D) effect of Chr on the cell cycle of MDSCs; (E) proliferation of CFSE‐labelled MDSCs, as determined by flow cytometry. Inducible nitric oxide synthase (iNOS), COX‐2, and Arg‐1 protein (F) and mRNA (G) levels in Chr‐treated MDSCs. Immunosuppressive function analysis of MDSCs after Chr treatment, including NO production (H), reactive oxygen species (ROS) level (I) and Arg‐1 activity (J). Data expressed as mean ± SD, n = 3. ns, not significant. *p < .05, **p < .01. Chr‐L, 10 µM; Chr‐H, 20 µM
FIGURE 2
FIGURE 2
Chrysin targeting RhoA/PI3K/AKT pathway inhibits myeloid‐derived suppressor cells (MDSCs) and exerts anti‐tumour effect: (A) Schematics show the treatments of tumour‐bearing C57BL6 mice; (B) representative photographs of transplanted tumours at the end of the experiment; mouse body weight (C), tumour volume (D) and tumour weight (E) change in each group; flow cytometry analysed the effect of Chr on the ratio of MDSCs (left) and CD8+ T cells (right) in the marrow (F) and spleen (G). Chr‐L, 20 mg/kg; Chr‐H, 40 mg/kg, n = 6; (H) enrichment analysis of GO and KEGG; (I) protein–protein interaction (PPI) network of differential genes in MDSCs; (J) the effects of Chr on RhoA, Akt and p‐Akt in G‐MDSC at the protein level, as detected by Western blot. Data expressed as mean ± SD. ns, not significant. *p < .05, **p < .01. Chr‐L, 10 µM; Chr‐H, 20 µM
FIGURE 3
FIGURE 3
Chrysin inhibits the promotion capability of myeloid‐derived suppressor cells (MDSCs) on tumour angiogenesis in vivo: (A) proteomic analysis of angiogenesis‐related pathways; (B and C) flow cytometric analysed the ratio of MDSCs in tumour and peripheral blood of B16‐F10 tumour‐bearing mice after Chr treatment; (D) flow cytometry was used to analyse CD8+ T cells infiltration in tumour tissues after Chr treatment; (E) representative image of immunohistochemistry (IHC) analysis of hypoxia‐inducible factor (HIF)‐1α expression in tumour tissues; (F) microvascular densities, vascular permeability and vascular perfusion changes in tumours of each group; (G) apoptosis evaluation by TUNEL assay in each group; (H) representative haematoxylin and eosin (HE) staining of tumours sections in each group. Quantification was performed on three random visual fields for each sample (three sample per group). Data expressed as mean ± SD. ns, not significant. *p < .05, **p < .01. Chr‐L, 20 mg/kg; Chr‐H, 40 mg/kg
FIGURE 4
FIGURE 4
Chrysin synergistically enhances the anti‐tumour activity of PD‐1 inhibitors: (A) representative photographs of transplanted tumours at the end of the experiment; change in mouse body weight (B), tumour volume (C) and tumour weight (D) after administration of Chr and PD‐1 Ab, whether alone or in combination; (E) survival curve of B16‐F10 tumour‐bearing mice after Chr and PD‐1 Ab were administered individually or in combination; (F) analysis of 4T1‐Luc tumour by live‐animal fluorescence imaging; change in mouse body weight (G), tumour volume (H) and tumour weight (I) after the administration of Chr and PD‐1 Ab in 4T1 tumour‐bearing BALB/C mice; (J) survival curve of 4T1 tumour‐bearing BALB/C mice after Chr and PD‐1 mAb were administered individually or in combination. Data expressed as mean ± SD, n = 6. ns, not significant. *p < .05, **p < .01. Chr‐H, 40 mg/kg; PD‐1 Ab, 10 mg/kg; Chr, 40 mg/kg + PD‐1 Ab, 10 mg/kg
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