Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance
Hepatocellular carcinoma (HCC) is highly malignant and prone to metastasize due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Programmed cell deaths (PCDs) including apoptosis, ferroptosis, and pyroptosis routinely occur in the HCC TME and participate in tumorigenesis. How...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-04-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.845974/full |
| _version_ | 1811311739532214272 |
|---|---|
| author | Yi Hu Yi Hu Dan Chen Minjing Hong Jing Liu Jing Liu Yijia Li Yijia Li Jianlei Hao Jianlei Hao Ligong Lu Zhinan Yin Zhinan Yin Yangzhe Wu |
| author_facet | Yi Hu Yi Hu Dan Chen Minjing Hong Jing Liu Jing Liu Yijia Li Yijia Li Jianlei Hao Jianlei Hao Ligong Lu Zhinan Yin Zhinan Yin Yangzhe Wu |
| author_sort | Yi Hu |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) is highly malignant and prone to metastasize due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Programmed cell deaths (PCDs) including apoptosis, ferroptosis, and pyroptosis routinely occur in the HCC TME and participate in tumorigenesis. However, how apoptosis, ferroptosis, and pyroptosis are involved in constructions of the immunosuppressive TME and their underlying cross-talk remains to be further unveiled. In this work, we deciphered the immunosuppressive landscape of HCC TME, which demonstrated high expressions of inhibitory checkpoint molecules and infiltration of protumor immune cells but low infiltration of antitumor effector immune cells. Further investigations unequivocally revealed that marker genes of apoptosis, ferroptosis, and pyroptosis are closely correlated with expressions and infiltrations of inhibitory checkpoint molecules and immune cells and that higher “-optosis” links to poorer patient prognosis. Notably, such three types of “-optosis” interact with each other at both the gene and protein levels, suggesting that they conspiringly induce the establishment of the immunosuppressive HCC TME. Interestingly, examinations of circulating γδ T cells in HCC patients revealed a noticeable dysfunction phenotype. The strikingly elevated ratio of the Vδ1+ versus the Vδ2+ subset suggested that the Vδ1+/Vδ2+ ratio would be a potential biomarker for the diagnosis and prognosis in HCC patients. Altogether, this work thoroughly decrypted the underlying correlations between apoptosis, ferroptosis, and pyroptosis and the formation of immunosuppressive HCC TME and, meanwhile, indicated that allogeneic Vδ2+ γδ T-cell transfer would be a promising adjuvant strategy for renormalizing circulating γδ T cell and thus achieving sound clinical efficacy against HCC. |
| first_indexed | 2024-04-13T10:23:11Z |
| format | Article |
| id | doaj.art-a4c4a59422d14242a60d6cfc2da351ce |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T10:23:11Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a4c4a59422d14242a60d6cfc2da351ce2022-12-22T02:50:25ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-04-011310.3389/fimmu.2022.845974845974Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell ImbalanceYi Hu0Yi Hu1Dan Chen2Minjing Hong3Jing Liu4Jing Liu5Yijia Li6Yijia Li7Jianlei Hao8Jianlei Hao9Ligong Lu10Zhinan Yin11Zhinan Yin12Yangzhe Wu13Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, ChinaMicrobiology and Immunology Department, School of Medicine, Faculty of Medical Science, Jinan University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, ChinaGuangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, ChinaGuangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, ChinaThe Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, ChinaThe Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, ChinaThe Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, ChinaGuangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, ChinaThe Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, ChinaHepatocellular carcinoma (HCC) is highly malignant and prone to metastasize due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Programmed cell deaths (PCDs) including apoptosis, ferroptosis, and pyroptosis routinely occur in the HCC TME and participate in tumorigenesis. However, how apoptosis, ferroptosis, and pyroptosis are involved in constructions of the immunosuppressive TME and their underlying cross-talk remains to be further unveiled. In this work, we deciphered the immunosuppressive landscape of HCC TME, which demonstrated high expressions of inhibitory checkpoint molecules and infiltration of protumor immune cells but low infiltration of antitumor effector immune cells. Further investigations unequivocally revealed that marker genes of apoptosis, ferroptosis, and pyroptosis are closely correlated with expressions and infiltrations of inhibitory checkpoint molecules and immune cells and that higher “-optosis” links to poorer patient prognosis. Notably, such three types of “-optosis” interact with each other at both the gene and protein levels, suggesting that they conspiringly induce the establishment of the immunosuppressive HCC TME. Interestingly, examinations of circulating γδ T cells in HCC patients revealed a noticeable dysfunction phenotype. The strikingly elevated ratio of the Vδ1+ versus the Vδ2+ subset suggested that the Vδ1+/Vδ2+ ratio would be a potential biomarker for the diagnosis and prognosis in HCC patients. Altogether, this work thoroughly decrypted the underlying correlations between apoptosis, ferroptosis, and pyroptosis and the formation of immunosuppressive HCC TME and, meanwhile, indicated that allogeneic Vδ2+ γδ T-cell transfer would be a promising adjuvant strategy for renormalizing circulating γδ T cell and thus achieving sound clinical efficacy against HCC.https://www.frontiersin.org/articles/10.3389/fimmu.2022.845974/fullapoptosispyroptosisferroptosisimmunosuppressive HCC TMEγδ T-cell imbalance |
| spellingShingle | Yi Hu Yi Hu Dan Chen Minjing Hong Jing Liu Jing Liu Yijia Li Yijia Li Jianlei Hao Jianlei Hao Ligong Lu Zhinan Yin Zhinan Yin Yangzhe Wu Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance Frontiers in Immunology apoptosis pyroptosis ferroptosis immunosuppressive HCC TME γδ T-cell imbalance |
| title | Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance |
| title_full | Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance |
| title_fullStr | Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance |
| title_full_unstemmed | Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance |
| title_short | Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance |
| title_sort | apoptosis pyroptosis and ferroptosis conspiringly induce immunosuppressive hepatocellular carcinoma microenvironment and γδ t cell imbalance |
| topic | apoptosis pyroptosis ferroptosis immunosuppressive HCC TME γδ T-cell imbalance |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.845974/full |
| work_keys_str_mv | AT yihu apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT yihu apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT danchen apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT minjinghong apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT jingliu apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT jingliu apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT yijiali apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT yijiali apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT jianleihao apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT jianleihao apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT ligonglu apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT zhinanyin apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT zhinanyin apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance AT yangzhewu apoptosispyroptosisandferroptosisconspiringlyinduceimmunosuppressivehepatocellularcarcinomamicroenvironmentandgdtcellimbalance |