Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses
The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepato...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Valerie Chew [verfasserIn] |
|---|
| Format: |
Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2017 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Proceedings of the National Academy of Sciences of the United States of America - Washington, DC : NAS, 1877, 114(2017), 29, Seite E5900 |
|---|---|
| Übergeordnetes Werk: |
volume:114 ; year:2017 ; number:29 ; pages:E5900 |
| Links: |
|---|
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OLC1998531007 |
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| 520 | |a The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T-cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed. | ||
| 650 | 4 | |a Macrophages | |
| 650 | 4 | |a Immunoregulation | |
| 650 | 4 | |a Tissues | |
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| 650 | 4 | |a Immune system | |
| 650 | 4 | |a Liver cancer | |
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| 650 | 4 | |a Exhaustion | |
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| 650 | 4 | |a Cell activation | |
| 650 | 4 | |a Dimensional analysis | |
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| 650 | 4 | |a Hepatocellular carcinoma | |
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| 650 | 4 | |a Cancer | |
| 650 | 4 | |a Cytometry | |
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PQ20171228 (DE-627)OLC1998531007 (DE-599)GBVOLC1998531007 (PRQ)p939-dde62daff11173546efcd6650f3a5ddef21978758afa0ad30777bc51bd0149a90 (KEY)0583363920170000114002905900delineationofanimmunosuppressivegradientinhepatoce DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Valerie Chew verfasserin aut Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T-cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed. Macrophages Immunoregulation Tissues CXCR3 protein Immune system Liver cancer Immunotherapy CCR6 protein Immunological memory Lymphocytes Exhaustion Tumor cells Cell activation Dimensional analysis Compartments CD4 antigen Antigens Foxp3 protein Proteomics Lymphocytes T CCL20 protein Hepatocellular carcinoma Composition effects CD223 antigen Immunology Leukocytes Recruitment Memory cells Natural killer cells Tumors Killer cells Immunofluorescence CD8 antigen Cancer Cytometry CXCL10 protein PD-1 protein Antigen (tumor-associated) Liyun Lai oth Lu Pan oth Chun Jye Lim oth Juntao Li oth Raymond Ong oth Camillus Chua oth Jing Yao Leong oth Kiat Hon Lim oth Han Chong Toh oth Ser Yee Lee oth Chung Yip Chan oth Brian K P Goh oth Alexander Chung oth Pierce K H Chow oth Salvatore Albani oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 29, Seite E5900 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:29 pages:E5900 https://search.proquest.com/docview/1946436049 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 29 E5900 |
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PQ20171228 (DE-627)OLC1998531007 (DE-599)GBVOLC1998531007 (PRQ)p939-dde62daff11173546efcd6650f3a5ddef21978758afa0ad30777bc51bd0149a90 (KEY)0583363920170000114002905900delineationofanimmunosuppressivegradientinhepatoce DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Valerie Chew verfasserin aut Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T-cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed. Macrophages Immunoregulation Tissues CXCR3 protein Immune system Liver cancer Immunotherapy CCR6 protein Immunological memory Lymphocytes Exhaustion Tumor cells Cell activation Dimensional analysis Compartments CD4 antigen Antigens Foxp3 protein Proteomics Lymphocytes T CCL20 protein Hepatocellular carcinoma Composition effects CD223 antigen Immunology Leukocytes Recruitment Memory cells Natural killer cells Tumors Killer cells Immunofluorescence CD8 antigen Cancer Cytometry CXCL10 protein PD-1 protein Antigen (tumor-associated) Liyun Lai oth Lu Pan oth Chun Jye Lim oth Juntao Li oth Raymond Ong oth Camillus Chua oth Jing Yao Leong oth Kiat Hon Lim oth Han Chong Toh oth Ser Yee Lee oth Chung Yip Chan oth Brian K P Goh oth Alexander Chung oth Pierce K H Chow oth Salvatore Albani oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 29, Seite E5900 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:29 pages:E5900 https://search.proquest.com/docview/1946436049 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 29 E5900 |
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PQ20171228 (DE-627)OLC1998531007 (DE-599)GBVOLC1998531007 (PRQ)p939-dde62daff11173546efcd6650f3a5ddef21978758afa0ad30777bc51bd0149a90 (KEY)0583363920170000114002905900delineationofanimmunosuppressivegradientinhepatoce DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Valerie Chew verfasserin aut Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T-cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed. Macrophages Immunoregulation Tissues CXCR3 protein Immune system Liver cancer Immunotherapy CCR6 protein Immunological memory Lymphocytes Exhaustion Tumor cells Cell activation Dimensional analysis Compartments CD4 antigen Antigens Foxp3 protein Proteomics Lymphocytes T CCL20 protein Hepatocellular carcinoma Composition effects CD223 antigen Immunology Leukocytes Recruitment Memory cells Natural killer cells Tumors Killer cells Immunofluorescence CD8 antigen Cancer Cytometry CXCL10 protein PD-1 protein Antigen (tumor-associated) Liyun Lai oth Lu Pan oth Chun Jye Lim oth Juntao Li oth Raymond Ong oth Camillus Chua oth Jing Yao Leong oth Kiat Hon Lim oth Han Chong Toh oth Ser Yee Lee oth Chung Yip Chan oth Brian K P Goh oth Alexander Chung oth Pierce K H Chow oth Salvatore Albani oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 29, Seite E5900 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:29 pages:E5900 https://search.proquest.com/docview/1946436049 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 29 E5900 |
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PQ20171228 (DE-627)OLC1998531007 (DE-599)GBVOLC1998531007 (PRQ)p939-dde62daff11173546efcd6650f3a5ddef21978758afa0ad30777bc51bd0149a90 (KEY)0583363920170000114002905900delineationofanimmunosuppressivegradientinhepatoce DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Valerie Chew verfasserin aut Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T-cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed. Macrophages Immunoregulation Tissues CXCR3 protein Immune system Liver cancer Immunotherapy CCR6 protein Immunological memory Lymphocytes Exhaustion Tumor cells Cell activation Dimensional analysis Compartments CD4 antigen Antigens Foxp3 protein Proteomics Lymphocytes T CCL20 protein Hepatocellular carcinoma Composition effects CD223 antigen Immunology Leukocytes Recruitment Memory cells Natural killer cells Tumors Killer cells Immunofluorescence CD8 antigen Cancer Cytometry CXCL10 protein PD-1 protein Antigen (tumor-associated) Liyun Lai oth Lu Pan oth Chun Jye Lim oth Juntao Li oth Raymond Ong oth Camillus Chua oth Jing Yao Leong oth Kiat Hon Lim oth Han Chong Toh oth Ser Yee Lee oth Chung Yip Chan oth Brian K P Goh oth Alexander Chung oth Pierce K H Chow oth Salvatore Albani oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 29, Seite E5900 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:29 pages:E5900 https://search.proquest.com/docview/1946436049 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 29 E5900 |
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PQ20171228 (DE-627)OLC1998531007 (DE-599)GBVOLC1998531007 (PRQ)p939-dde62daff11173546efcd6650f3a5ddef21978758afa0ad30777bc51bd0149a90 (KEY)0583363920170000114002905900delineationofanimmunosuppressivegradientinhepatoce DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Valerie Chew verfasserin aut Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T-cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed. Macrophages Immunoregulation Tissues CXCR3 protein Immune system Liver cancer Immunotherapy CCR6 protein Immunological memory Lymphocytes Exhaustion Tumor cells Cell activation Dimensional analysis Compartments CD4 antigen Antigens Foxp3 protein Proteomics Lymphocytes T CCL20 protein Hepatocellular carcinoma Composition effects CD223 antigen Immunology Leukocytes Recruitment Memory cells Natural killer cells Tumors Killer cells Immunofluorescence CD8 antigen Cancer Cytometry CXCL10 protein PD-1 protein Antigen (tumor-associated) Liyun Lai oth Lu Pan oth Chun Jye Lim oth Juntao Li oth Raymond Ong oth Camillus Chua oth Jing Yao Leong oth Kiat Hon Lim oth Han Chong Toh oth Ser Yee Lee oth Chung Yip Chan oth Brian K P Goh oth Alexander Chung oth Pierce K H Chow oth Salvatore Albani oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 29, Seite E5900 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:29 pages:E5900 https://search.proquest.com/docview/1946436049 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 29 E5900 |
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Valerie Chew @@aut@@ Liyun Lai @@oth@@ Lu Pan @@oth@@ Chun Jye Lim @@oth@@ Juntao Li @@oth@@ Raymond Ong @@oth@@ Camillus Chua @@oth@@ Jing Yao Leong @@oth@@ Kiat Hon Lim @@oth@@ Han Chong Toh @@oth@@ Ser Yee Lee @@oth@@ Chung Yip Chan @@oth@@ Brian K P Goh @@oth@@ Alexander Chung @@oth@@ Pierce K H Chow @@oth@@ Salvatore Albani @@oth@@ |
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Valerie Chew ddc 500 ddc 570 fid LING fid BIODIV misc Macrophages misc Immunoregulation misc Tissues misc CXCR3 protein misc Immune system misc Liver cancer misc Immunotherapy misc CCR6 protein misc Immunological memory misc Lymphocytes misc Exhaustion misc Tumor cells misc Cell activation misc Dimensional analysis misc Compartments misc CD4 antigen misc Antigens misc Foxp3 protein misc Proteomics misc Lymphocytes T misc CCL20 protein misc Hepatocellular carcinoma misc Composition effects misc CD223 antigen misc Immunology misc Leukocytes misc Recruitment misc Memory cells misc Natural killer cells misc Tumors misc Killer cells misc Immunofluorescence misc CD8 antigen misc Cancer misc Cytometry misc CXCL10 protein misc PD-1 protein misc Antigen (tumor-associated) Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses |
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500 DE-101 570 AVZ LING fid BIODIV fid Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses Macrophages Immunoregulation Tissues CXCR3 protein Immune system Liver cancer Immunotherapy CCR6 protein Immunological memory Lymphocytes Exhaustion Tumor cells Cell activation Dimensional analysis Compartments CD4 antigen Antigens Foxp3 protein Proteomics Lymphocytes T CCL20 protein Hepatocellular carcinoma Composition effects CD223 antigen Immunology Leukocytes Recruitment Memory cells Natural killer cells Tumors Killer cells Immunofluorescence CD8 antigen Cancer Cytometry CXCL10 protein PD-1 protein Antigen (tumor-associated) |
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delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses |
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Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses |
| abstract |
The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T-cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed. |
| abstractGer |
The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T-cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed. |
| abstract_unstemmed |
The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T-cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed. |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a2200265 4500</leader><controlfield tag="001">OLC1998531007</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230715082412.0</controlfield><controlfield tag="007">tu</controlfield><controlfield tag="008">171125s2017 xx ||||| 00| ||eng c</controlfield><datafield tag="028" ind1="5" ind2="2"><subfield code="a">PQ20171228</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)OLC1998531007</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)GBVOLC1998531007</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(PRQ)p939-dde62daff11173546efcd6650f3a5ddef21978758afa0ad30777bc51bd0149a90</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(KEY)0583363920170000114002905900delineationofanimmunosuppressivegradientinhepatoce</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">500</subfield><subfield code="q">DE-101</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">570</subfield><subfield code="q">AVZ</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">LING</subfield><subfield code="2">fid</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">BIODIV</subfield><subfield code="2">fid</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Valerie Chew</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2017</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">ohne Hilfsmittel zu benutzen</subfield><subfield code="b">n</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Band</subfield><subfield code="b">nc</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T-cell subset responsive to anti-PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Macrophages</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Immunoregulation</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Tissues</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">CXCR3 protein</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Immune system</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Liver cancer</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Immunotherapy</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">CCR6 protein</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Immunological memory</subfield></datafield><datafield 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