Mitochondrial metabolic reprogramming of macrophages and T cells enhances CD47 antibody-engineered oncolytic virus antitumor immunity
Background Although immunotherapy can reinvigorate immune cells to clear tumors, the response rates are poor in some patients. Here, CD47 antibody-engineered oncolytic viruses (oAd-αCD47) were employed to lyse tumors and activate immunity. The oAd-αCD47 induced comprehensive remodeling of the tumor...
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BMJ Publishing Group
2024-12-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/12/e009768.full |
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| author | Ping Cheng Shichuan Hu Zhongbing Qi Xianglin Xu Xiangyu Long Anliang Huang Jiyan Liu |
| author_facet | Ping Cheng Shichuan Hu Zhongbing Qi Xianglin Xu Xiangyu Long Anliang Huang Jiyan Liu |
| author_sort | Ping Cheng |
| collection | DOAJ |
| description | Background Although immunotherapy can reinvigorate immune cells to clear tumors, the response rates are poor in some patients. Here, CD47 antibody-engineered oncolytic viruses (oAd-αCD47) were employed to lyse tumors and activate immunity. The oAd-αCD47 induced comprehensive remodeling of the tumor microenvironment (TME). However, whether the acidic TME affects the antitumor immunotherapeutic effects of oncolytic viruses-αCD47 has not been clarified.Methods To assess the impact of oAd-αCD47 treatment on the TME, we employed multicolor flow cytometry. Glucose uptake was quantified using 2NBDG, while mitochondrial content was evaluated with MitoTracker FM dye. pH imaging of tumors was performed using the pH-sensitive fluorophore SNARF-4F. Moreover, changes in the calmodulin-dependent protein kinase II (CaMKII)/cyclic AMP activates-responsive element-binding proteins (CREB) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) signaling pathway were confirmed through western blotting and flow cytometry.Results Here, we identified sodium bicarbonate (NaBi) as the potent metabolic reprogramming agent that enhanced antitumor responses in the acidic TME. The combination of NaBi and oAd-αCD47 therapy significantly inhibited tumor growth and produced complete immune control in various tumor-bearing mouse models. Mechanistically, combination therapy mainly reduced the number of regulatory T cells and enriched the ratio of M1-type macrophages TAMs (M1.TAMs) to M2-type macrophages TAMs (M2.TAMs), while decreasing the abundance of PD-1+TIM3+ expression and increasing the expression of CD107a in the CD8+ T cells. Furthermore, the combination therapy enhanced the metabolic function of T cells and macrophages by upregulating PGC1α, a key regulator of mitochondrial biogenesis. This metabolic improvement contributed to a robust antitumor response. Notably, the combination therapy also promoted the generation of memory T cells, suggesting its potential as an effective neoadjuvant treatment for preventing postoperative tumor recurrence and metastasis.Conclusions Tumor acidic microenvironment impairs mitochondrial energy metabolism in macrophages and T cells inducing oAd-αCD47 immunotherapeutic resistance. NaBi improves the acidity of the TME and activates the CaMKII/CREB/PGC1α mitochondrial biosynthesis signaling pathway, which reprograms the energy metabolism of macrophages and T cells in the TME, and oral NaBi enhances the antitumor effect of oAd-αCD47. |
| format | Article |
| id | doaj-art-ea041a1eee9c4639beaddf5c8911df12 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ea041a1eee9c4639beaddf5c8911df122024-12-16T15:00:41ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-12-01121210.1136/jitc-2024-009768Mitochondrial metabolic reprogramming of macrophages and T cells enhances CD47 antibody-engineered oncolytic virus antitumor immunityPing Cheng0Shichuan Hu1Zhongbing Qi2Xianglin Xu3Xiangyu Long4Anliang Huang5Jiyan Liu6Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Oncology, Guangan People’s Hospital, Sichuan, Guangan, ChinaDepartment of Pathology, Chengdu Fifth People`s Hospital, Chengdu, ChinaDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaBackground Although immunotherapy can reinvigorate immune cells to clear tumors, the response rates are poor in some patients. Here, CD47 antibody-engineered oncolytic viruses (oAd-αCD47) were employed to lyse tumors and activate immunity. The oAd-αCD47 induced comprehensive remodeling of the tumor microenvironment (TME). However, whether the acidic TME affects the antitumor immunotherapeutic effects of oncolytic viruses-αCD47 has not been clarified.Methods To assess the impact of oAd-αCD47 treatment on the TME, we employed multicolor flow cytometry. Glucose uptake was quantified using 2NBDG, while mitochondrial content was evaluated with MitoTracker FM dye. pH imaging of tumors was performed using the pH-sensitive fluorophore SNARF-4F. Moreover, changes in the calmodulin-dependent protein kinase II (CaMKII)/cyclic AMP activates-responsive element-binding proteins (CREB) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) signaling pathway were confirmed through western blotting and flow cytometry.Results Here, we identified sodium bicarbonate (NaBi) as the potent metabolic reprogramming agent that enhanced antitumor responses in the acidic TME. The combination of NaBi and oAd-αCD47 therapy significantly inhibited tumor growth and produced complete immune control in various tumor-bearing mouse models. Mechanistically, combination therapy mainly reduced the number of regulatory T cells and enriched the ratio of M1-type macrophages TAMs (M1.TAMs) to M2-type macrophages TAMs (M2.TAMs), while decreasing the abundance of PD-1+TIM3+ expression and increasing the expression of CD107a in the CD8+ T cells. Furthermore, the combination therapy enhanced the metabolic function of T cells and macrophages by upregulating PGC1α, a key regulator of mitochondrial biogenesis. This metabolic improvement contributed to a robust antitumor response. Notably, the combination therapy also promoted the generation of memory T cells, suggesting its potential as an effective neoadjuvant treatment for preventing postoperative tumor recurrence and metastasis.Conclusions Tumor acidic microenvironment impairs mitochondrial energy metabolism in macrophages and T cells inducing oAd-αCD47 immunotherapeutic resistance. NaBi improves the acidity of the TME and activates the CaMKII/CREB/PGC1α mitochondrial biosynthesis signaling pathway, which reprograms the energy metabolism of macrophages and T cells in the TME, and oral NaBi enhances the antitumor effect of oAd-αCD47.https://jitc.bmj.com/content/12/12/e009768.full |
| spellingShingle | Ping Cheng Shichuan Hu Zhongbing Qi Xianglin Xu Xiangyu Long Anliang Huang Jiyan Liu Mitochondrial metabolic reprogramming of macrophages and T cells enhances CD47 antibody-engineered oncolytic virus antitumor immunity Journal for ImmunoTherapy of Cancer |
| title | Mitochondrial metabolic reprogramming of macrophages and T cells enhances CD47 antibody-engineered oncolytic virus antitumor immunity |
| title_full | Mitochondrial metabolic reprogramming of macrophages and T cells enhances CD47 antibody-engineered oncolytic virus antitumor immunity |
| title_fullStr | Mitochondrial metabolic reprogramming of macrophages and T cells enhances CD47 antibody-engineered oncolytic virus antitumor immunity |
| title_full_unstemmed | Mitochondrial metabolic reprogramming of macrophages and T cells enhances CD47 antibody-engineered oncolytic virus antitumor immunity |
| title_short | Mitochondrial metabolic reprogramming of macrophages and T cells enhances CD47 antibody-engineered oncolytic virus antitumor immunity |
| title_sort | mitochondrial metabolic reprogramming of macrophages and t cells enhances cd47 antibody engineered oncolytic virus antitumor immunity |
| url | https://jitc.bmj.com/content/12/12/e009768.full |
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