Resveratrol amplifies the anti-tumor effect of α-PD-1 by altering the intestinal microbiome and PGD2 content
Patients with pancreatic cancer (PC) receive limited benefits from immune checkpoint inhibitors (ICIs) alone. Recent studies have indicated that the combination of intestinal microflora regulators and ICI may be an effective strategy for enhancing the response to tumor immunotherapy. Resveratrol has...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Gut Microbes |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19490976.2024.2447821 |
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| author | Baohua Luo Qingling An Jingyu Lei Dengxu Tan Xiaoqiu Liu Hui Li Yong Zhao Jing Qin Caiqin Zhang Yongbin Zhang Changhong Shi |
| author_facet | Baohua Luo Qingling An Jingyu Lei Dengxu Tan Xiaoqiu Liu Hui Li Yong Zhao Jing Qin Caiqin Zhang Yongbin Zhang Changhong Shi |
| author_sort | Baohua Luo |
| collection | DOAJ |
| description | Patients with pancreatic cancer (PC) receive limited benefits from immune checkpoint inhibitors (ICIs) alone. Recent studies have indicated that the combination of intestinal microflora regulators and ICI may be an effective strategy for enhancing the response to tumor immunotherapy. Resveratrol has been shown to regulate both intestinal microbiota and the immune microenvironment; therefore, we speculated that resveratrol may enhance the immunotherapeutic effect of α-PD-1 on PC. We constructed a double-humanized mouse model with both a humanized immune system and PC to evaluate the efficacy of different doses of resveratrol combined with anti-PD-1 mAb therapy and analyze the characteristics of the tumor immune microenvironment after treatment. In addition, I6S sequencing was performed on mouse fecal samples, and metabolomic analyses were performed on plasma samples to understand the characteristics of the intestinal microbiome and metabolites to explore the potential mechanism of anti-tumor immunity mediated by combined immunotherapy. Results suggested that the combination of resveratrol with anti-PD-1 mAb promoted the infiltration and activation of CD8+ T cells in tumor tissues, thus effectively inhibiting PC growth. Attentively, the effect emphasized the combined effect, dose-dependent nature and the involvement of gut microbiome. Furthermore, metabonomics showed that the combination therapy significantly increased the abundance of the metabolite prostaglandin D2 (PGD2), which was most likely related to the increased abundance of Desulfovibrio fairfieldensis. Finally, we confirmed that PGD2 amplified anti-tumor effect of α-PD-1 by activating prostaglandin D receptor 1 (DP1) to promote CD8 infiltration in double humanized PC mice and subcutaneously transplanted KPC mice. Overall, our data revealed resveratrol has the potential to enhance the efficacy of α-PD-1 by regulating the gut microbiome and its metabolites, and PGD2 was an effective molecular mediating the infiltration of CD8+T cells into tumor tissue to amplify the anti-tumor effect of α-PD-1.Significance The anti-PD-1 mAb may be further considered along with PGD2 or active molecules that can promote PGD2 synthesis to enhance the anti-tumor immune response |
| format | Article |
| id | doaj-art-fca00f80055b4b6ea2dc76bad9c364de |
| institution | Kabale University |
| issn | 1949-0976 1949-0984 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Gut Microbes |
| spelling | doaj-art-fca00f80055b4b6ea2dc76bad9c364de2025-01-06T20:16:08ZengTaylor & Francis GroupGut Microbes1949-09761949-09842025-12-0117110.1080/19490976.2024.2447821Resveratrol amplifies the anti-tumor effect of α-PD-1 by altering the intestinal microbiome and PGD2 contentBaohua Luo0Qingling An1Jingyu Lei2Dengxu Tan3Xiaoqiu Liu4Hui Li5Yong Zhao6Jing Qin7Caiqin Zhang8Yongbin Zhang9Changhong Shi10Division of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, Xi’an, Shaanxi, P.R. ChinaDivision of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, Xi’an, Shaanxi, P.R. ChinaSchool of Basic Medicine, Medical College of Yan’an University, Yan’an, P.R. ChinaDivision of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, Xi’an, Shaanxi, P.R. ChinaScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, P.R. ChinaSchool of Basic Medicine, Medical College of Yan’an University, Yan’an, P.R. ChinaDivision of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, Xi’an, Shaanxi, P.R. ChinaDivision of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, Xi’an, Shaanxi, P.R. ChinaDivision of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, Xi’an, Shaanxi, P.R. ChinaLaboratory Animal Center, Guangzhou University of Chinese Medicine, Guangzhou, P.R. ChinaDivision of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, Xi’an, Shaanxi, P.R. ChinaPatients with pancreatic cancer (PC) receive limited benefits from immune checkpoint inhibitors (ICIs) alone. Recent studies have indicated that the combination of intestinal microflora regulators and ICI may be an effective strategy for enhancing the response to tumor immunotherapy. Resveratrol has been shown to regulate both intestinal microbiota and the immune microenvironment; therefore, we speculated that resveratrol may enhance the immunotherapeutic effect of α-PD-1 on PC. We constructed a double-humanized mouse model with both a humanized immune system and PC to evaluate the efficacy of different doses of resveratrol combined with anti-PD-1 mAb therapy and analyze the characteristics of the tumor immune microenvironment after treatment. In addition, I6S sequencing was performed on mouse fecal samples, and metabolomic analyses were performed on plasma samples to understand the characteristics of the intestinal microbiome and metabolites to explore the potential mechanism of anti-tumor immunity mediated by combined immunotherapy. Results suggested that the combination of resveratrol with anti-PD-1 mAb promoted the infiltration and activation of CD8+ T cells in tumor tissues, thus effectively inhibiting PC growth. Attentively, the effect emphasized the combined effect, dose-dependent nature and the involvement of gut microbiome. Furthermore, metabonomics showed that the combination therapy significantly increased the abundance of the metabolite prostaglandin D2 (PGD2), which was most likely related to the increased abundance of Desulfovibrio fairfieldensis. Finally, we confirmed that PGD2 amplified anti-tumor effect of α-PD-1 by activating prostaglandin D receptor 1 (DP1) to promote CD8 infiltration in double humanized PC mice and subcutaneously transplanted KPC mice. Overall, our data revealed resveratrol has the potential to enhance the efficacy of α-PD-1 by regulating the gut microbiome and its metabolites, and PGD2 was an effective molecular mediating the infiltration of CD8+T cells into tumor tissue to amplify the anti-tumor effect of α-PD-1.Significance The anti-PD-1 mAb may be further considered along with PGD2 or active molecules that can promote PGD2 synthesis to enhance the anti-tumor immune responsehttps://www.tandfonline.com/doi/10.1080/19490976.2024.2447821Resveratrolimmune checkpoint inhibitorsintestinal microbiotaprostaglandin D2pancreatic cancer |
| spellingShingle | Baohua Luo Qingling An Jingyu Lei Dengxu Tan Xiaoqiu Liu Hui Li Yong Zhao Jing Qin Caiqin Zhang Yongbin Zhang Changhong Shi Resveratrol amplifies the anti-tumor effect of α-PD-1 by altering the intestinal microbiome and PGD2 content Gut Microbes Resveratrol immune checkpoint inhibitors intestinal microbiota prostaglandin D2 pancreatic cancer |
| title | Resveratrol amplifies the anti-tumor effect of α-PD-1 by altering the intestinal microbiome and PGD2 content |
| title_full | Resveratrol amplifies the anti-tumor effect of α-PD-1 by altering the intestinal microbiome and PGD2 content |
| title_fullStr | Resveratrol amplifies the anti-tumor effect of α-PD-1 by altering the intestinal microbiome and PGD2 content |
| title_full_unstemmed | Resveratrol amplifies the anti-tumor effect of α-PD-1 by altering the intestinal microbiome and PGD2 content |
| title_short | Resveratrol amplifies the anti-tumor effect of α-PD-1 by altering the intestinal microbiome and PGD2 content |
| title_sort | resveratrol amplifies the anti tumor effect of α pd 1 by altering the intestinal microbiome and pgd2 content |
| topic | Resveratrol immune checkpoint inhibitors intestinal microbiota prostaglandin D2 pancreatic cancer |
| url | https://www.tandfonline.com/doi/10.1080/19490976.2024.2447821 |
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