TNFα modulates PANX1 activation to promote ATP release and enhance P2RX7-mediated antitumor immune responses after chemotherapy in colorectal cancer
Abstract ATP and its receptor P2RX7 exert a pivotal effect on antitumor immunity during chemotherapy-induced immunogenic cell death (ICD). Here, we demonstrated that TNFα-mediated PANX1 cleavage was essential for ATP release in response to chemotherapy in colorectal cancer (CRC). TNFα promoted PANX1...
| Main Authors: | , , , , , , , , , , , |
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| Formato: | Artigo |
| Idioma: | English |
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Nature Publishing Group
2024-01-01
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| Colecção: | Cell Death and Disease |
| Acesso em linha: | https://doi.org/10.1038/s41419-023-06408-5 |
| _version_ | 1827381947233468416 |
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| author | Kevin Chih-Yang Huang Shu-Fen Chiang Pei-Chun Lin Wei-Ze Hong Pei-Chen Yang Hui-Ping Chang Shin-Lei Peng Tsung-Wei Chen Tao-Wei Ke Ji-An Liang William Tzu-Liang Chen K. S. Clifford Chao |
| author_facet | Kevin Chih-Yang Huang Shu-Fen Chiang Pei-Chun Lin Wei-Ze Hong Pei-Chen Yang Hui-Ping Chang Shin-Lei Peng Tsung-Wei Chen Tao-Wei Ke Ji-An Liang William Tzu-Liang Chen K. S. Clifford Chao |
| author_sort | Kevin Chih-Yang Huang |
| collection | DOAJ |
| description | Abstract ATP and its receptor P2RX7 exert a pivotal effect on antitumor immunity during chemotherapy-induced immunogenic cell death (ICD). Here, we demonstrated that TNFα-mediated PANX1 cleavage was essential for ATP release in response to chemotherapy in colorectal cancer (CRC). TNFα promoted PANX1 cleavage via a caspase 8/3-dependent pathway to enhance cancer cell immunogenicity, leading to dendritic cell maturation and T-cell activation. Blockade of the ATP receptor P2RX7 by the systemic administration of small molecules significantly attenuated the therapeutic efficacy of chemotherapy and decreased the infiltration of immune cells. In contrast, administration of an ATP mimic markedly increased the therapeutic efficacy of chemotherapy and enhanced the infiltration of immune cells in vivo. High PANX1 expression was positively correlated with the recruitment of DCs and T cells within the tumor microenvironment and was associated with favorable survival outcomes in CRC patients who received adjuvant chemotherapy. Furthermore, a loss-of-function P2RX7 mutation was associated with reduced infiltration of CD8+ immune cells and poor survival outcomes in patients. Taken together, these results reveal that TNFα-mediated PANX1 cleavage promotes ATP-P2RX7 signaling and is a key determinant of chemotherapy-induced antitumor immunity. |
| first_indexed | 2024-03-08T14:12:22Z |
| format | Article |
| id | doaj.art-9b94d1b51f6c4247a382ea20f1a4efd8 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-08T14:12:22Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-9b94d1b51f6c4247a382ea20f1a4efd82024-01-14T12:38:38ZengNature Publishing GroupCell Death and Disease2041-48892024-01-0115111410.1038/s41419-023-06408-5TNFα modulates PANX1 activation to promote ATP release and enhance P2RX7-mediated antitumor immune responses after chemotherapy in colorectal cancerKevin Chih-Yang Huang0Shu-Fen Chiang1Pei-Chun Lin2Wei-Ze Hong3Pei-Chen Yang4Hui-Ping Chang5Shin-Lei Peng6Tsung-Wei Chen7Tao-Wei Ke8Ji-An Liang9William Tzu-Liang Chen10K. S. Clifford Chao11Department of Biomedical Imaging and Radiological Science, China Medical UniversityLab of Precision Medicine, Feng-Yuan Hospital, Ministry of Health and WelfareProton Therapy and Science Center, China Medical University Hospital, China Medical UniversityProton Therapy and Science Center, China Medical University Hospital, China Medical UniversityProton Therapy and Science Center, China Medical University Hospital, China Medical UniversityProton Therapy and Science Center, China Medical University Hospital, China Medical UniversityDepartment of Biomedical Imaging and Radiological Science, China Medical UniversityDepartment of Pathology, Asia University Hospital, Asia UniversitySchool of Chinese Medicine and Graduate Institute of Chinese Medicine, China Medical UniversityDepartment of Radiation Oncology, China Medical University Hospital, China Medical UniversityDepartment of Colorectal Surgery, China Medical University Hospital, China Medical UniversityProton Therapy and Science Center, China Medical University Hospital, China Medical UniversityAbstract ATP and its receptor P2RX7 exert a pivotal effect on antitumor immunity during chemotherapy-induced immunogenic cell death (ICD). Here, we demonstrated that TNFα-mediated PANX1 cleavage was essential for ATP release in response to chemotherapy in colorectal cancer (CRC). TNFα promoted PANX1 cleavage via a caspase 8/3-dependent pathway to enhance cancer cell immunogenicity, leading to dendritic cell maturation and T-cell activation. Blockade of the ATP receptor P2RX7 by the systemic administration of small molecules significantly attenuated the therapeutic efficacy of chemotherapy and decreased the infiltration of immune cells. In contrast, administration of an ATP mimic markedly increased the therapeutic efficacy of chemotherapy and enhanced the infiltration of immune cells in vivo. High PANX1 expression was positively correlated with the recruitment of DCs and T cells within the tumor microenvironment and was associated with favorable survival outcomes in CRC patients who received adjuvant chemotherapy. Furthermore, a loss-of-function P2RX7 mutation was associated with reduced infiltration of CD8+ immune cells and poor survival outcomes in patients. Taken together, these results reveal that TNFα-mediated PANX1 cleavage promotes ATP-P2RX7 signaling and is a key determinant of chemotherapy-induced antitumor immunity.https://doi.org/10.1038/s41419-023-06408-5 |
| spellingShingle | Kevin Chih-Yang Huang Shu-Fen Chiang Pei-Chun Lin Wei-Ze Hong Pei-Chen Yang Hui-Ping Chang Shin-Lei Peng Tsung-Wei Chen Tao-Wei Ke Ji-An Liang William Tzu-Liang Chen K. S. Clifford Chao TNFα modulates PANX1 activation to promote ATP release and enhance P2RX7-mediated antitumor immune responses after chemotherapy in colorectal cancer Cell Death and Disease |
| title | TNFα modulates PANX1 activation to promote ATP release and enhance P2RX7-mediated antitumor immune responses after chemotherapy in colorectal cancer |
| title_full | TNFα modulates PANX1 activation to promote ATP release and enhance P2RX7-mediated antitumor immune responses after chemotherapy in colorectal cancer |
| title_fullStr | TNFα modulates PANX1 activation to promote ATP release and enhance P2RX7-mediated antitumor immune responses after chemotherapy in colorectal cancer |
| title_full_unstemmed | TNFα modulates PANX1 activation to promote ATP release and enhance P2RX7-mediated antitumor immune responses after chemotherapy in colorectal cancer |
| title_short | TNFα modulates PANX1 activation to promote ATP release and enhance P2RX7-mediated antitumor immune responses after chemotherapy in colorectal cancer |
| title_sort | tnfα modulates panx1 activation to promote atp release and enhance p2rx7 mediated antitumor immune responses after chemotherapy in colorectal cancer |
| url | https://doi.org/10.1038/s41419-023-06408-5 |
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