Weitiao No. 3 (微调3号方) enhances the efficacy of anti-programmed cell death protein-1 immunotherapy by modulating the intestinal microbiota in an orthotopic model of gastric cancer mice

doi:10.19852/j.cnki.jtcm.2024.05.002

Abstract

Abstract:

OBJECTIVE: To explore the effects of Weitiao No. 3 (微调3号方, WD-3) on anti-programmed cell death protein-1 (PD-1) immunotherapy in gastric cancer (GC).

METHODS: The intestinal microbiota was analyzed by 16S rDNA sequencing of fecal samples from three groups: healthy people (Health), GC patients (GC), and WD-3-treated GC patients (WD-3). Next, we established an orthotopic model of GC mice, which were treated with anti-PD-1, WD-3, or an inoculation of intestinal bacteria. Immune markers CD3, CD4, CD8, and forkhead box protein P3 (FOXP3), and the cell proliferation marker Ki67, were evaluated by immunohistochemistry. Cell apoptosis in GC tumors was assessed by terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling staining. Enzyme-linked immunosorbent assays (ELISAs) were performed to analyze the serum levels of the following cytokines in GC mice: tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-6, IL-10, interferon (IFN)-γ, and transforming growth factor (TGF)-β.

RESULTS: Sequencing data showed that there were significant differences in the composition of the gut microbial community among the three human groups. The gut bacteria in the three groups mainly comprised the phyla Firmicutes, Proteobacteria, Bacteroidetes, and Actinobacteria. At the genus level, the relative abundances of Bifidobacterium and Coprococcus showed significant decreases in the GC group, and an obvious increase in the WD-3 group, compared with the Health group. Interestingly, the relative abundance of Saccharopolyspora was only detected in the WD-3 group. The results of in vivo experiments in GC mice showed that WD-3 or anti-PD-1 treatment increased the levels of CD3+, CD4+, and CD8+ T cells, but decreased the levels of FOXP3+ regulatory T cells. Furthermore, WD-3 or PD-1 antibody treatment inhibited proliferation and promoted apoptosis of GC tumor cells. ELISA analysis showed that WD-3 or PD-1 antibody treatment facilitated TNF-α, IL-2, and IFN-γ expression, while suppressing IL-6, IL-10, and TGF-β expression. Combination therapy with WD-3 and anti-PD-1 intensified all of these effects.

CONCLUSION: WD-3 enhanced the immunotherapeutic efficacy of anti-PD-1 by modulating the intestinal microbiota in an orthotopic model of GC mice.

Key words: stomach neoplasms, immunotherapy, programmed cell death 1 receptor, gastrointestinal microbiome, Weitiao No. 3

HUANG Xiaona, LI Yuzhen, ZHU Chenyang, ZHU Hengzhou, JIANG Chenyu, ZHU Xiaodan, ZHANG Chencen, JIN Chunhui. Weitiao No. 3 (微调3号方) enhances the efficacy of anti-programmed cell death protein-1 immunotherapy by modulating the intestinal microbiota in an orthotopic model of gastric cancer mice[J]. Journal of Traditional Chinese Medicine, 2024, 44(5): 906-915.

Figures/Tables 9

Figure 1 Effects of WD-3 on the composition of the intestinal microbiota Venn diagram of OTUs in the three groups (Health, GC, and WD-3). Health group: healthy participants; GC group: GC patients. WD-3 group: GC patients treated with WD-3. GC: gastric cancer; WD-3: Weitiao No. 3; OTUs: operational taxonomic units.

Figure 2 Cluster heat map of the top 50 bacteria in terms of average abundance at the genus level Health group: healthy participants; GC group: GC patients. WD-3 group: GC patients treated with WD-3. GC: gastric cancer; WD-3: Weitiao No. 3.

Table 1 Relative abundances of Bifidobacterium, Coprococcus, and Saccharopolyspora in the three groups (%, $\bar{x}±s$)

Group	n	Bifidobacterium	Coprococcus	Saccharopolyspora
Health	10	20.266±11.387	4.553±3.543	0.000±0.000
GC	17	2.099±2.821^a	0.249±0.271^a	0.000±0.000
WD-3	12	24.541±20.546^b	1.214±0.379^b	0.044±0.017^b

Figure 3 Effects of WD-3 on the efficacy of immunotherapy in GC mice A: IHC staining. Magnification × 200; Scar bar = 20 μm. A1: CD3 expression in the control group; A2: CD3 expression in the anti-PD-1 group; A3: CD3 expression in the WD-3 group; A4: CD3 expression in the anti-PD-1 + WD-3 group; A5: CD4 expression in the control group; A6: CD4 expression in the anti-PD-1 group; A7: CD4 expression in the WD-3 group; A8: CD4 expression in the anti-PD-1+WD-3 group; A9: CD8 expression in the control group; A10: CD8 expression in the anti-PD-1 group; A11: CD8 expression in the WD-3 group; A12: CD8 expression in the anti-PD-1+WD-3 group; A13: FOXP3 expression in the control group; A14: FOXP3 expression in the anti-PD-1 group; A15: FOXP3 expression in the WD-3 group; A16: FOXP3 expression in the anti-PD-1 + WD-3 group; A17: Ki67 expression in the control group; A18: Ki67 expression in the anti-PD-1 group; A19: Ki67 expression in the WD-3 group; A20: Ki67 expression in the anti-PD-1 + WD-3 group; B: TUNEL staining was used to detect cell apoptosis of GC tissues. Magnification × 200; Scar bar = 20 μm. B1: cell apoptosis in the control group; B2: cell apoptosis in the anti-PD-1 group; B3: cell apoptosis in the WD-3 group; B4: cell apoptosis in the anti-PD-1 + WD-3 group. Control group: GC mice with normal saline; anti-PD-1 group: GC mice treated with PD-1 inhibitor; WD-3 group: GC mice treated with WD-3; anti-PD-1+WD-3 group: GC mice treated with PD-1 inhibitor and WD-3. GC: gastric cancer; anti-PD-1: anti-programmed cell death protein-1; WD-3: Weitiao No. 3; IHC: immunohistochemistry; TUNEL: terminal-deoxynucleotidyl-transferase -mediated deoxyuridine triphosphate nick end labeling; FOXP3: forkhead box protein P3.

Table 2 Mean optical density for Immunohistochemistry ($\bar{x}±s$)

Group	n	CD3	CD4	CD8	FOXP3	Ki67
Control	6	0.106±0.016	0.084±0.02	0.089±0.020	0.300±0.040	0.309±0.036
Anti-PD-1	6	0.244±0.0279^a	0.145±0.025^a	0.156±0.028^a	0.161±0.029^a	0.162±0.025^a
WD-3	6	0.201±0.026^a	0.128±0.021^a	0.131±0.016^a	0.247±0.029^a	0.244±0.020^a
Anti-PD-1+WD-3	6	0.414±0.034^abc	0.221±0.031^abc	0.210±0.035^abc	0.078±0.015^abc	0.102±0.023^abc

Table 3 Inflammatory factor concentration (pg/mL, $\bar{x}±s$)

Group	n	TNF-α	IL-2	IL-6	IL-10	IFN-γ	TGF-β
Control	6	33.6±2.9	28.8±3.1	203.8±10.1	65.2±7.5	186.4±5.7	226.0±6.2
Anti-PD-1	6	59.5±5.1^a	45.8±3.9^a	116.9±11.1^a	40.8±3.1^a	314.1±12.7^a	166.0±4.8^a
WD-3	6	54.7±4.4^a	42.5±2.7^a	129.7±16.7^a	43.7±5.9^a	298.6±17.2^a	175.6±11.7^a
Anti-PD-1+WD-3	6	83.9±8.7^abc	64.2±5.2^abc	80.8±11.9^abc	32.8±6.1^ade	353.0±6.4^abc	124.4±11.8^abc

Figure 4 Effects of intestinal flora on the efficacy of immunotherapy in GC mice A: IHC staining. Magnification × 100; Scar bar = 50 μm. A1: CD3 expression in the control group; A2: CD3 expression in the anti-PD-1 group; A3: CD3 expression in the intestinal flora group; A4: CD3 expression in the anti-PD-1 + intestinal flora group; A5: CD4 expression in the control group; A6: CD4 expression in the anti-PD-1 group; A7: CD4 expression in the intestinal flora group; A8: CD4 expression in the anti-PD-1 + intestinal flora group; A9: CD8 expression in the control group; A10: CD8 expression in the anti-PD-1 group; A11: CD8 expression in the intestinal flora group; A12: CD8 expression in the anti-PD-1 + intestinal flora group; A13: FOXP3 expression in the control group; A14: FOXP3 expression in the anti-PD-1 group; A15: FOXP3 expression in the intestinal flora group; A16: FOXP3 expression in the anti-PD-1+ intestinal flora group; A17: Ki67 expression in the control group; A18: Ki67 expression in the anti-PD-1 group; A19: Ki67 expression in the intestinal flora group; A20: Ki67 expression in the anti-PD-1 + intestinal flora group.; B: TUNEL staining was used to detect the cell apoptosis of GC tumors. Magnification × 100; Scar bar = 50 μm. B1: cell apoptosis in the control group; B2: cell apoptosis in the anti-PD-1 group; B3: cell apoptosis in the intestinal flora group; B4: cell apoptosis in the anti-PD-1+ intestinal flora group. Control group: GC mice with normal saline; anti-PD-1 group: GC mice treated with PD-1 inhibitor; intestinal flora group: GC mice treated with intestinal flora; anti-PD-1 + intestinal flora group: GC mice treated with PD-1 inhibitor and intestinal flora. GC: gastric cancer; anti-PD-1: anti-programmed cell death protein-1; IHC: immunohistochemistry; TUNEL: terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling; FOXP3: forkhead box protein P3.

Table 4 Mean optical density for Immunohistochemistry ($\bar{x}±s$)

Group	n	CD3	CD4	CD8	FOXP3	Ki67
Control	6	0.101±0.014	0.086±0.013	0.045±0.013	0.306±0.017	0.299±0.016
Anti-PD-1	6	0.304±0.030^a	0.262±0.034^a	0.155±0.016^a	0.165±0.018^a	0.152±0.021^a
Intestinal flora	6	0.219±0.022^a	0.153±0.011^a	0.103±0.011^a	0.213±0.012^a	0.218±0.037^a
Anti-PD-1+ intestinal flora	6	0.528±0.018^abc	0.404±0.019^abc	0.221±0.016^abc	0.057±0.011^abc	0.056±0.013^abc

Table 5 Inflammatory factor concentration (pg/mL, $\bar{x}±s$)

Group	n	TNF-α	IL-2	IL-6	IL-10	IFN-γ	TGF-β
Control	6	36.0±3.4	31.8±4.4	231.0±7.4	75.3±2.7	190.8±7.3	234.9±3.8
Anti-PD-1	6	66.8±2.6^a	59.8±4.3^a	114.8±11.2^a	40.4±3.7^a	340.0±4.0^a	164.6±7.7^a
Intestinal flora	6	51.7±3.2^a	47.5±3.0^a	174.1±13.5^a	56.9±5.4^a	293.0±5.9^a	197.7±3.8^a
Anti-PD-1+ intestinal flora	6	99.4±1.9^abc	85.2±2.7^abc	52.5±11.6^abc	23.7±6.0^adc	446.1±12.5^abc	115.8±6.4^abc

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