IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma
Background We have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased prog...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2020-05-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/1/e000285.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850197334807281664 |
|---|---|
| author | Yang Liu Hui Yang Yun Chen Wei Sun Zhongyi Yan Wenjie Zhang Yongliang Yao Runqiu Jiang |
| author_facet | Yang Liu Hui Yang Yun Chen Wei Sun Zhongyi Yan Wenjie Zhang Yongliang Yao Runqiu Jiang |
| author_sort | Yang Liu |
| collection | DOAJ |
| description | Background We have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1 (PD-L1) in both the peripheral monocytes and tumor-infiltrating macrophages of human hepatocellular carcinoma (HCC).Methods The expression and correlation of all the indices were explored in monocytes and tumor-infiltrating macrophages within both human and mice HCC. The mechanic regulations were studied by using both in vitro and in vivo studies.Results We found a significant decrease in PTPRO in HCC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumor-associated macrophages (TAMs) in HCC. Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with HCC and were associated with increased T-cell exhaustion (Tim3+T cells). A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways. Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/miR-25–3 p axis. Monocytes and TAMs showed significantly increased miR-25–3 p expression, which could target the 3′ untranslated region of PTPRO. The miR-25–3 p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in HCC monocytes. IL-6/STAT3/c-MYC activation enhanced in vitro miR-25–3 p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25–3 p–modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1–induced immunosuppression in an orthotopic tumor transplantation model.Conclusions Increased serum IL-6 downregulated PTPRO expression in HCC monocytes and macrophages by activating STAT3/c-MYC/miR-25–3 p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling. |
| format | Article |
| id | doaj-art-83c6d33710cd4d07950c5c31dc0b9f8c |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-83c6d33710cd4d07950c5c31dc0b9f8c2025-08-20T02:13:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2019-000285IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinomaYang Liu0Hui Yang1Yun Chen2Wei Sun3Zhongyi Yan4Wenjie Zhang5Yongliang Yao6Runqiu Jiang7National Clinical Research Center for Child Health and Disorders, Chongqing, China3 Nanyue Biopharmaceutical Corporation Ltd, Nanyue, China2 Department of Immunology, Nanjing Medical University, Nanjing, ChinaDepartment of Cardiology, the Second Hospital of Jilin University, Changchun, Jilin, China2 Department of Immunology, Nanjing Medical University, Nanjing, China1 Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China5 Department of Clinical Laboratory, Kunshan First People`s Hospital, Affiliated to Jiangsu University, Kunshan, China1 Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, ChinaBackground We have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1 (PD-L1) in both the peripheral monocytes and tumor-infiltrating macrophages of human hepatocellular carcinoma (HCC).Methods The expression and correlation of all the indices were explored in monocytes and tumor-infiltrating macrophages within both human and mice HCC. The mechanic regulations were studied by using both in vitro and in vivo studies.Results We found a significant decrease in PTPRO in HCC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumor-associated macrophages (TAMs) in HCC. Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with HCC and were associated with increased T-cell exhaustion (Tim3+T cells). A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways. Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/miR-25–3 p axis. Monocytes and TAMs showed significantly increased miR-25–3 p expression, which could target the 3′ untranslated region of PTPRO. The miR-25–3 p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in HCC monocytes. IL-6/STAT3/c-MYC activation enhanced in vitro miR-25–3 p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25–3 p–modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1–induced immunosuppression in an orthotopic tumor transplantation model.Conclusions Increased serum IL-6 downregulated PTPRO expression in HCC monocytes and macrophages by activating STAT3/c-MYC/miR-25–3 p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling.https://jitc.bmj.com/content/8/1/e000285.full |
| spellingShingle | Yang Liu Hui Yang Yun Chen Wei Sun Zhongyi Yan Wenjie Zhang Yongliang Yao Runqiu Jiang IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma Journal for ImmunoTherapy of Cancer |
| title | IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma |
| title_full | IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma |
| title_fullStr | IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma |
| title_full_unstemmed | IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma |
| title_short | IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma |
| title_sort | il 6 promotes pd l1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type o expression in human hepatocellular carcinoma |
| url | https://jitc.bmj.com/content/8/1/e000285.full |
| work_keys_str_mv | AT yangliu il6promotespdl1expressioninmonocytesandmacrophagesbydecreasingproteintyrosinephosphatasereceptortypeoexpressioninhumanhepatocellularcarcinoma AT huiyang il6promotespdl1expressioninmonocytesandmacrophagesbydecreasingproteintyrosinephosphatasereceptortypeoexpressioninhumanhepatocellularcarcinoma AT yunchen il6promotespdl1expressioninmonocytesandmacrophagesbydecreasingproteintyrosinephosphatasereceptortypeoexpressioninhumanhepatocellularcarcinoma AT weisun il6promotespdl1expressioninmonocytesandmacrophagesbydecreasingproteintyrosinephosphatasereceptortypeoexpressioninhumanhepatocellularcarcinoma AT zhongyiyan il6promotespdl1expressioninmonocytesandmacrophagesbydecreasingproteintyrosinephosphatasereceptortypeoexpressioninhumanhepatocellularcarcinoma AT wenjiezhang il6promotespdl1expressioninmonocytesandmacrophagesbydecreasingproteintyrosinephosphatasereceptortypeoexpressioninhumanhepatocellularcarcinoma AT yongliangyao il6promotespdl1expressioninmonocytesandmacrophagesbydecreasingproteintyrosinephosphatasereceptortypeoexpressioninhumanhepatocellularcarcinoma AT runqiujiang il6promotespdl1expressioninmonocytesandmacrophagesbydecreasingproteintyrosinephosphatasereceptortypeoexpressioninhumanhepatocellularcarcinoma |