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Research Articles

Enriched HLA-E and CD94/NKG2A Interaction Limits Antitumor CD8+ Tumor-Infiltrating T Lymphocyte Responses

Megat Abd Hamid, Ruo-Zheng Wang, Xuan Yao, Peiwen Fan, Xi Li, Xue-Mei Chang, Yaning Feng, Stephanie Jones, David Maldonado-Perez, Craig Waugh, Clare Verrill, Alison Simmons, Vincenzo Cerundolo, Andrew McMichael, Christopher Conlon, Xiyan Wang, Yanchun Peng and Tao Dong
Megat Abd Hamid
1CAMS-Oxford International Centre for Translational Immunology, CAMS Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
2MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
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  • ORCID record for Megat Abd Hamid
Ruo-Zheng Wang
3Chinese Academy of Medical Sciences (CAMS) Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Urumqi, China.
4Third Affiliated Hospital, Xinjiang Tumor Hospital, Urumqi, China.
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  • For correspondence: tao.dong@imm.ox.ac.uk wrz8526@163.com
Xuan Yao
1CAMS-Oxford International Centre for Translational Immunology, CAMS Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
2MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
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Peiwen Fan
3Chinese Academy of Medical Sciences (CAMS) Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Urumqi, China.
4Third Affiliated Hospital, Xinjiang Tumor Hospital, Urumqi, China.
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Xi Li
1CAMS-Oxford International Centre for Translational Immunology, CAMS Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
2MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
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Xue-Mei Chang
3Chinese Academy of Medical Sciences (CAMS) Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Urumqi, China.
4Third Affiliated Hospital, Xinjiang Tumor Hospital, Urumqi, China.
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Yaning Feng
3Chinese Academy of Medical Sciences (CAMS) Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Urumqi, China.
4Third Affiliated Hospital, Xinjiang Tumor Hospital, Urumqi, China.
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Stephanie Jones
5Oxford Radcliffe Biobank, Department of Cellular Pathology, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
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  • ORCID record for Stephanie Jones
David Maldonado-Perez
5Oxford Radcliffe Biobank, Department of Cellular Pathology, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
6Oxford NIHR Biomedical Research Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.
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Craig Waugh
7Flow Cytometry Facility, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
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Clare Verrill
5Oxford Radcliffe Biobank, Department of Cellular Pathology, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
6Oxford NIHR Biomedical Research Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.
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Alison Simmons
1CAMS-Oxford International Centre for Translational Immunology, CAMS Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
2MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
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Vincenzo Cerundolo
1CAMS-Oxford International Centre for Translational Immunology, CAMS Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
2MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
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Andrew McMichael
1CAMS-Oxford International Centre for Translational Immunology, CAMS Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
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Christopher Conlon
1CAMS-Oxford International Centre for Translational Immunology, CAMS Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
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Xiyan Wang
2MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
4Third Affiliated Hospital, Xinjiang Tumor Hospital, Urumqi, China.
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Yanchun Peng
1CAMS-Oxford International Centre for Translational Immunology, CAMS Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
2MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
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Tao Dong
1CAMS-Oxford International Centre for Translational Immunology, CAMS Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
2MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
3Chinese Academy of Medical Sciences (CAMS) Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Urumqi, China.
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  • For correspondence: tao.dong@imm.ox.ac.uk wrz8526@163.com
DOI: 10.1158/2326-6066.CIR-18-0885 Published August 2019
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Abstract

Immunotherapy treatments with anti-PD-1 boost recovery in less than 30% of treated cancer patients, indicating the complexity of the tumor microenvironment. Expression of HLA-E is linked to poor clinical outcomes in mice and human patients. However, the contributions to immune evasion of HLA-E, a ligand for the inhibitory CD94/NKG2A receptor, when expressed on tumors, compared with adjacent tissue and peripheral blood mononuclear cells, remains unclear. In this study, we report that epithelial-derived cancer cells, tumor macrophages, and CD141+ conventional dendritic cells (cDC) contributed to HLA-E enrichment in carcinomas. Different cancer types showed a similar pattern of enrichment. Enrichment correlated to NKG2A upregulation on CD8+ tumor-infiltrating T lymphocytes (TIL) but not on CD4+ TILs. CD94/NKG2A is exclusively expressed on PD-1high TILs while lacking intratumoral CD103 expression. We also found that the presence of CD94/NKG2A on human tumor–specific T cells impairs IL2 receptor–dependent proliferation, which affects IFNγ-mediated responses and antitumor cytotoxicity. These functionalities recover following antibody-mediated blockade in vitro and ex vivo. Our results suggest that enriched HLA-E:CD94/NKG2A inhibitory interaction can impair survival of PD-1high TILs in the tumor microenvironment.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2019;7:1293–306

  • Received December 10, 2018.
  • Revision received March 6, 2019.
  • Accepted June 13, 2019.
  • Published first June 18, 2019.
  • ©2019 American Association for Cancer Research.
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Cancer Immunology Research: 7 (8)
August 2019
Volume 7, Issue 8
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Enriched HLA-E and CD94/NKG2A Interaction Limits Antitumor CD8+ Tumor-Infiltrating T Lymphocyte Responses
Megat Abd Hamid, Ruo-Zheng Wang, Xuan Yao, Peiwen Fan, Xi Li, Xue-Mei Chang, Yaning Feng, Stephanie Jones, David Maldonado-Perez, Craig Waugh, Clare Verrill, Alison Simmons, Vincenzo Cerundolo, Andrew McMichael, Christopher Conlon, Xiyan Wang, Yanchun Peng and Tao Dong
Cancer Immunol Res August 1 2019 (7) (8) 1293-1306; DOI: 10.1158/2326-6066.CIR-18-0885

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Enriched HLA-E and CD94/NKG2A Interaction Limits Antitumor CD8+ Tumor-Infiltrating T Lymphocyte Responses
Megat Abd Hamid, Ruo-Zheng Wang, Xuan Yao, Peiwen Fan, Xi Li, Xue-Mei Chang, Yaning Feng, Stephanie Jones, David Maldonado-Perez, Craig Waugh, Clare Verrill, Alison Simmons, Vincenzo Cerundolo, Andrew McMichael, Christopher Conlon, Xiyan Wang, Yanchun Peng and Tao Dong
Cancer Immunol Res August 1 2019 (7) (8) 1293-1306; DOI: 10.1158/2326-6066.CIR-18-0885
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