Downregulation of phosphoserine phosphatase potentiates tumor immune environments to enhance immune checkpoint blockade therapy
Background Effects of immune checkpoint blockade (ICB) treatment in hepatocellular carcinoma (HCC) are limited. The current study explored the possibility of exploiting tumor metabolic switches to enhance HCC sensitivity to immune therapies.Methods Levels of one-carbon (1C) metabolism and the expres...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/2/e005986.full |
| _version_ | 1797893070893613056 |
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| author | Yan Wu Da Jiang Zhi-Peng Peng Xing-Chen Liu Yong-Hao Ruan Ai-Qi Huang Wan-Ru Ning Ze-Zhou Jiang Limin Zheng |
| author_facet | Yan Wu Da Jiang Zhi-Peng Peng Xing-Chen Liu Yong-Hao Ruan Ai-Qi Huang Wan-Ru Ning Ze-Zhou Jiang Limin Zheng |
| author_sort | Yan Wu |
| collection | DOAJ |
| description | Background Effects of immune checkpoint blockade (ICB) treatment in hepatocellular carcinoma (HCC) are limited. The current study explored the possibility of exploiting tumor metabolic switches to enhance HCC sensitivity to immune therapies.Methods Levels of one-carbon (1C) metabolism and the expression of phosphoserine phosphatase (PSPH), an upstream enzyme of 1C pathway, were evaluated in paired non-tumor and tumor tissues from HCC. Underlying mechanisms mediating the role of PSPH in regulating the infiltration of monocytes/macrophages and CD8+ T lymphocytes were studied through both in vitro and in vivo experiments.Results PSPH was significantly upregulated in tumor tissues of HCC and its levels were positively correlated with disease progression. PSPH knockdown inhibited tumor growth in immunocompetent mice, but not in those with macrophage or T lymphocyte deficiencies, indicating the pro-tumor effects of PSPH were dependent on both immune components. Mechanistically, PSPH facilitated monocytes/macrophages infiltration by inducing the production of C-C motif chemokine 2 (CCL2), while at the same time reduced CD8+ T lymphocytes recruitment through inhibiting the production of C-X-C Motif Chemokine 10 (CXCL10) in tumor necrosis factor alpha (TNF-α)-conditioned cancer cells. Glutathione and S-adenosyl-methionine were partially involved in regulating the production of CCL2 and CXCL10, respectively. shPSPH (short hairpin RNA) transfection of cancer cells enhanced tumor sensitivity to anti-programmed cell death protein 1 (PD-1) therapy in vivo, and interestingly, metformin could inhibit PSPH expression in cancer cells and mimic the effects of shPSPH in sensitizing tumors to anti-PD-1 treatment.Conclusions By tilting the immune balance towards a tumor-friendly composition, PSPH might be useful both as a marker in stratifying patients for ICB therapy, and as an attractive therapeutic target in the treatment of human HCC. |
| first_indexed | 2024-04-10T06:47:04Z |
| format | Article |
| id | doaj.art-3a0bd449e6924afc8c637214e3bb6f61 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-10T06:47:04Z |
| publishDate | 2023-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-3a0bd449e6924afc8c637214e3bb6f612023-02-28T11:30:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-02-0111210.1136/jitc-2022-005986Downregulation of phosphoserine phosphatase potentiates tumor immune environments to enhance immune checkpoint blockade therapyYan Wu0Da Jiang1Zhi-Peng Peng2Xing-Chen Liu3Yong-Hao Ruan4Ai-Qi Huang5Wan-Ru Ning6Ze-Zhou Jiang7Limin Zheng8Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-Sen University, Guangzhou, ChinaGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-Sen University, Guangzhou, ChinaGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-Sen University, Guangzhou, ChinaGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-Sen University, Guangzhou, ChinaGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-Sen University, Guangzhou, ChinaGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-Sen University, Guangzhou, ChinaGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-Sen University, Guangzhou, ChinaGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-Sen University, Guangzhou, ChinaGuangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-Sen University, Guangzhou, ChinaBackground Effects of immune checkpoint blockade (ICB) treatment in hepatocellular carcinoma (HCC) are limited. The current study explored the possibility of exploiting tumor metabolic switches to enhance HCC sensitivity to immune therapies.Methods Levels of one-carbon (1C) metabolism and the expression of phosphoserine phosphatase (PSPH), an upstream enzyme of 1C pathway, were evaluated in paired non-tumor and tumor tissues from HCC. Underlying mechanisms mediating the role of PSPH in regulating the infiltration of monocytes/macrophages and CD8+ T lymphocytes were studied through both in vitro and in vivo experiments.Results PSPH was significantly upregulated in tumor tissues of HCC and its levels were positively correlated with disease progression. PSPH knockdown inhibited tumor growth in immunocompetent mice, but not in those with macrophage or T lymphocyte deficiencies, indicating the pro-tumor effects of PSPH were dependent on both immune components. Mechanistically, PSPH facilitated monocytes/macrophages infiltration by inducing the production of C-C motif chemokine 2 (CCL2), while at the same time reduced CD8+ T lymphocytes recruitment through inhibiting the production of C-X-C Motif Chemokine 10 (CXCL10) in tumor necrosis factor alpha (TNF-α)-conditioned cancer cells. Glutathione and S-adenosyl-methionine were partially involved in regulating the production of CCL2 and CXCL10, respectively. shPSPH (short hairpin RNA) transfection of cancer cells enhanced tumor sensitivity to anti-programmed cell death protein 1 (PD-1) therapy in vivo, and interestingly, metformin could inhibit PSPH expression in cancer cells and mimic the effects of shPSPH in sensitizing tumors to anti-PD-1 treatment.Conclusions By tilting the immune balance towards a tumor-friendly composition, PSPH might be useful both as a marker in stratifying patients for ICB therapy, and as an attractive therapeutic target in the treatment of human HCC.https://jitc.bmj.com/content/11/2/e005986.full |
| spellingShingle | Yan Wu Da Jiang Zhi-Peng Peng Xing-Chen Liu Yong-Hao Ruan Ai-Qi Huang Wan-Ru Ning Ze-Zhou Jiang Limin Zheng Downregulation of phosphoserine phosphatase potentiates tumor immune environments to enhance immune checkpoint blockade therapy Journal for ImmunoTherapy of Cancer |
| title | Downregulation of phosphoserine phosphatase potentiates tumor immune environments to enhance immune checkpoint blockade therapy |
| title_full | Downregulation of phosphoserine phosphatase potentiates tumor immune environments to enhance immune checkpoint blockade therapy |
| title_fullStr | Downregulation of phosphoserine phosphatase potentiates tumor immune environments to enhance immune checkpoint blockade therapy |
| title_full_unstemmed | Downregulation of phosphoserine phosphatase potentiates tumor immune environments to enhance immune checkpoint blockade therapy |
| title_short | Downregulation of phosphoserine phosphatase potentiates tumor immune environments to enhance immune checkpoint blockade therapy |
| title_sort | downregulation of phosphoserine phosphatase potentiates tumor immune environments to enhance immune checkpoint blockade therapy |
| url | https://jitc.bmj.com/content/11/2/e005986.full |
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