Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patients
BackgroundProgrammed cell death-1 (PD-1) immune checkpoint inhibitors are not effective in treating all patients with hepatocellular carcinoma (HCC), and regulatory T cells (Tregs) may determine the resistance to anti-PD-1 therapy.MethodsPatients were divided into two groups based on the clinical ef...
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| Format: | Article |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.960066/full |
| _version_ | 1818160552683241472 |
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| author | Jinren Zhou Qing Shao Yunjie Lu Yu Li Zibo Xu Bo Zhou Qiuyang Chen Xiangyu Li Xiaozhang Xu Yufeng Pan Yufeng Pan Zhenhua Deng Yiming Wang Yue Yu Jian Gu |
| author_facet | Jinren Zhou Qing Shao Yunjie Lu Yu Li Zibo Xu Bo Zhou Qiuyang Chen Xiangyu Li Xiaozhang Xu Yufeng Pan Yufeng Pan Zhenhua Deng Yiming Wang Yue Yu Jian Gu |
| author_sort | Jinren Zhou |
| collection | DOAJ |
| description | BackgroundProgrammed cell death-1 (PD-1) immune checkpoint inhibitors are not effective in treating all patients with hepatocellular carcinoma (HCC), and regulatory T cells (Tregs) may determine the resistance to anti-PD-1 therapy.MethodsPatients were divided into two groups based on the clinical efficacy of anti-PD-1 therapy. Flow cytometry was used to determine the phenotype of CD4+, CD8+, and Tregs in peripheral blood mononuclear cells (PBMCs). CD4+CD45RA+T cells were sorted to analyze Treg differentiation and function.ResultsNo significant differences were found between resistant and sensitive patients in the percentage of CD4+ T cells and Tregs in PBMCs or the differentiation and function of induced Tregs (iTregs). However, iTregs from resistant patients presented higher monocarboxylate transporter (MCT) expression. Lactate induced more iTregs and improved OXPHOS levels in the resistant group. MCT1 and MCT2 were highly expressed in tumor-infiltrating Tregs, and patients with higher MCT1 expression had worse clinical outcomes. Combinatorial therapy with MCT antibody and anti-PD-1 therapy effectively inhibited tumor growth.ConclusionMCT and its downstream lactate signal in Tregs can confer anti-PD-1 resistance and may be a marker of poor prognosis in HCC. |
| first_indexed | 2024-12-11T16:03:42Z |
| format | Article |
| id | doaj.art-50b80117683a4905a309fdf895da6b96 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-11T16:03:42Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-50b80117683a4905a309fdf895da6b962022-12-22T00:59:15ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-07-011210.3389/fonc.2022.960066960066Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patientsJinren Zhou0Qing Shao1Yunjie Lu2Yu Li3Zibo Xu4Bo Zhou5Qiuyang Chen6Xiangyu Li7Xiaozhang Xu8Yufeng Pan9Yufeng Pan10Zhenhua Deng11Yiming Wang12Yue Yu13Jian Gu14Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaLiver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Hepatobiliary Surgery, The First People's Hospital of Changzhou, The Third Hospital Affiliated to Soochow University, Changzhou, ChinaLiver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaLiver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of General Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, ChinaLiver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaLiver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaLiver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaLiver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaSchool of Medicine, Southeast University, Nanjing, ChinaLiver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaLiver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaLiver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaLiver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaBackgroundProgrammed cell death-1 (PD-1) immune checkpoint inhibitors are not effective in treating all patients with hepatocellular carcinoma (HCC), and regulatory T cells (Tregs) may determine the resistance to anti-PD-1 therapy.MethodsPatients were divided into two groups based on the clinical efficacy of anti-PD-1 therapy. Flow cytometry was used to determine the phenotype of CD4+, CD8+, and Tregs in peripheral blood mononuclear cells (PBMCs). CD4+CD45RA+T cells were sorted to analyze Treg differentiation and function.ResultsNo significant differences were found between resistant and sensitive patients in the percentage of CD4+ T cells and Tregs in PBMCs or the differentiation and function of induced Tregs (iTregs). However, iTregs from resistant patients presented higher monocarboxylate transporter (MCT) expression. Lactate induced more iTregs and improved OXPHOS levels in the resistant group. MCT1 and MCT2 were highly expressed in tumor-infiltrating Tregs, and patients with higher MCT1 expression had worse clinical outcomes. Combinatorial therapy with MCT antibody and anti-PD-1 therapy effectively inhibited tumor growth.ConclusionMCT and its downstream lactate signal in Tregs can confer anti-PD-1 resistance and may be a marker of poor prognosis in HCC.https://www.frontiersin.org/articles/10.3389/fonc.2022.960066/fullhepatocellular carcinomamonocarboxylate transporterlactateregulatory T cellstreatment resistance |
| spellingShingle | Jinren Zhou Qing Shao Yunjie Lu Yu Li Zibo Xu Bo Zhou Qiuyang Chen Xiangyu Li Xiaozhang Xu Yufeng Pan Yufeng Pan Zhenhua Deng Yiming Wang Yue Yu Jian Gu Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patients Frontiers in Oncology hepatocellular carcinoma monocarboxylate transporter lactate regulatory T cells treatment resistance |
| title | Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patients |
| title_full | Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patients |
| title_fullStr | Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patients |
| title_full_unstemmed | Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patients |
| title_short | Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patients |
| title_sort | monocarboxylate transporter upregulation in induced regulatory t cells promotes resistance to anti pd 1 therapy in hepatocellular carcinoma patients |
| topic | hepatocellular carcinoma monocarboxylate transporter lactate regulatory T cells treatment resistance |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.960066/full |
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