High-dose ascorbic acid synergizes with anti-PD1 therapy in non-small cell lung cancer in vitro and in vivo models
IntroductionImmune checkpoint inhibitors(ICIs) targeting programmed cell death protein 1 (PD1) confer significant survival benefits to patients with non-small cell lung cancer (NSCLC). However, there remains a substantial unmet need to identify therapeutic approaches to overcome resistance and provi...
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Frontiers Media S.A.
2025-01-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1512605/full |
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| author | Hak Su Kim Seung-hyun Kwon Ok Kyung Choi Taekyu Lim Taekyu Lim |
| author_facet | Hak Su Kim Seung-hyun Kwon Ok Kyung Choi Taekyu Lim Taekyu Lim |
| author_sort | Hak Su Kim |
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| description | IntroductionImmune checkpoint inhibitors(ICIs) targeting programmed cell death protein 1 (PD1) confer significant survival benefits to patients with non-small cell lung cancer (NSCLC). However, there remains a substantial unmet need to identify therapeutic approaches to overcome resistance and provide benefits to these patients. High-dose ascorbic acid (AA) acts synergistically with many standard anticancer treatments. However, little is known about the effect of high-dose AA on improving the efficacy of anti-PD1 inhibitors in NSCLC. This study aimed to elucidate the effects of high-dose AA on anti-PD1 immunotherapy in NSCLC.MethodsThe combined effects of high-dose AA and anti-PD1 were investigated using a coculture model of H460 cells and CD8+ T cells and an LLC1 lung cancer syngeneic mouse model. To investigate the molecular mechanism, tumor tissues from mice were analyzed by comprehensive proteomic profiling using nano-LC-ESI-MS/MS.ResultsPretreatment with a high dose of AA led to enhanced the sensitivity to the cytotoxicity of CD8+ T cells derived from healthy donor for H460 cells. Additionally, the combination of anti-PD1 and high-dose AA significantly increased CD8+ T cell cytotoxicity in H460 cells. The combination of anti-PD1 and high-dose AA showed dramatic antitumor effects in a syngeneic mouse model of lung cancer by significantly reducing tumor growth and increasing CD8+ T cell-dependent cytotoxicity and macrophage activity. Comprehensive protein analysis confirmed that high-dose AA in anti-PD1-treated tumor tissues enhanced the antitumor effects by regulating various immune-related mechanisms, including the B cell and T cell receptor signaling pathways, Fc gamma R-mediated phagocytosis, and natural killer (NK) cell-mediated cytotoxicity.DiscussionOur results suggest that high-dose AA may be a promising adjuvant to potentiate the efficacy of anti-PD1 immunotherapy. |
| format | Article |
| id | doaj-art-89b355638eed496c9be559000afa975b |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-89b355638eed496c9be559000afa975b2025-01-17T12:51:51ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.15126051512605High-dose ascorbic acid synergizes with anti-PD1 therapy in non-small cell lung cancer in vitro and in vivo modelsHak Su Kim0Seung-hyun Kwon1Ok Kyung Choi2Taekyu Lim3Taekyu Lim4Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of KoreaVeterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of KoreaVeterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of KoreaVeterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of KoreaDivision of Hematology-Oncology, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, Republic of KoreaIntroductionImmune checkpoint inhibitors(ICIs) targeting programmed cell death protein 1 (PD1) confer significant survival benefits to patients with non-small cell lung cancer (NSCLC). However, there remains a substantial unmet need to identify therapeutic approaches to overcome resistance and provide benefits to these patients. High-dose ascorbic acid (AA) acts synergistically with many standard anticancer treatments. However, little is known about the effect of high-dose AA on improving the efficacy of anti-PD1 inhibitors in NSCLC. This study aimed to elucidate the effects of high-dose AA on anti-PD1 immunotherapy in NSCLC.MethodsThe combined effects of high-dose AA and anti-PD1 were investigated using a coculture model of H460 cells and CD8+ T cells and an LLC1 lung cancer syngeneic mouse model. To investigate the molecular mechanism, tumor tissues from mice were analyzed by comprehensive proteomic profiling using nano-LC-ESI-MS/MS.ResultsPretreatment with a high dose of AA led to enhanced the sensitivity to the cytotoxicity of CD8+ T cells derived from healthy donor for H460 cells. Additionally, the combination of anti-PD1 and high-dose AA significantly increased CD8+ T cell cytotoxicity in H460 cells. The combination of anti-PD1 and high-dose AA showed dramatic antitumor effects in a syngeneic mouse model of lung cancer by significantly reducing tumor growth and increasing CD8+ T cell-dependent cytotoxicity and macrophage activity. Comprehensive protein analysis confirmed that high-dose AA in anti-PD1-treated tumor tissues enhanced the antitumor effects by regulating various immune-related mechanisms, including the B cell and T cell receptor signaling pathways, Fc gamma R-mediated phagocytosis, and natural killer (NK) cell-mediated cytotoxicity.DiscussionOur results suggest that high-dose AA may be a promising adjuvant to potentiate the efficacy of anti-PD1 immunotherapy.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1512605/fullanti-PD1high-dose ascorbic acidnon-small cell lung cancerimmune checkpoint inhibitorsproteomic analysis |
| spellingShingle | Hak Su Kim Seung-hyun Kwon Ok Kyung Choi Taekyu Lim Taekyu Lim High-dose ascorbic acid synergizes with anti-PD1 therapy in non-small cell lung cancer in vitro and in vivo models Frontiers in Immunology anti-PD1 high-dose ascorbic acid non-small cell lung cancer immune checkpoint inhibitors proteomic analysis |
| title | High-dose ascorbic acid synergizes with anti-PD1 therapy in non-small cell lung cancer in vitro and in vivo models |
| title_full | High-dose ascorbic acid synergizes with anti-PD1 therapy in non-small cell lung cancer in vitro and in vivo models |
| title_fullStr | High-dose ascorbic acid synergizes with anti-PD1 therapy in non-small cell lung cancer in vitro and in vivo models |
| title_full_unstemmed | High-dose ascorbic acid synergizes with anti-PD1 therapy in non-small cell lung cancer in vitro and in vivo models |
| title_short | High-dose ascorbic acid synergizes with anti-PD1 therapy in non-small cell lung cancer in vitro and in vivo models |
| title_sort | high dose ascorbic acid synergizes with anti pd1 therapy in non small cell lung cancer in vitro and in vivo models |
| topic | anti-PD1 high-dose ascorbic acid non-small cell lung cancer immune checkpoint inhibitors proteomic analysis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1512605/full |
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