Frontiers in Oncology (Oct 2019)
A Comprehensive Analysis of Key Immune Checkpoint Receptors on Tumor-Infiltrating T Cells From Multiple Types of Cancer
- Xi Li,
- Xi Li,
- Xi Li,
- Rouzheng Wang,
- Rouzheng Wang,
- Rouzheng Wang,
- Peiwen Fan,
- Peiwen Fan,
- Xuan Yao,
- Xuan Yao,
- Ling Qin,
- Yanchun Peng,
- Yanchun Peng,
- Miaomiao Ma,
- Miaomiao Ma,
- Neil Asley,
- Xuimei Chang,
- Xuimei Chang,
- Yaning Feng,
- Yaning Feng,
- Yunhui Hu,
- Yunhui Hu,
- Yonghong Zhang,
- Chris Li,
- Gregory Fanning,
- Stephanie Jones,
- Clare Verrill,
- David Maldonado-Perez,
- Paul Sopp,
- Craig Waugh,
- Stephen Taylor,
- Simon Mcgowan,
- Vincenzo Cerundolo,
- Vincenzo Cerundolo,
- Christopher Conlon,
- Andrew McMichael,
- Shichun Lu,
- Xiyan Wang,
- Xiyan Wang,
- Ning Li,
- Tao Dong,
- Tao Dong
Affiliations
- Xi Li
- Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Chinese Academy of Medical Sciences (CAMS), Xinjiang Medical University, Ürümqi, China
- Xi Li
- Nuffield Department of Medicine (NDM), Chinese Academy of Medical Sciences Oxford Institute (CAMS Oxford Institute), University of Oxford, Oxford, United Kingdom
- Xi Li
- MRC Human Immunology Unit, Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Rouzheng Wang
- Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Chinese Academy of Medical Sciences (CAMS), Xinjiang Medical University, Ürümqi, China
- Rouzheng Wang
- Nuffield Department of Medicine (NDM), Chinese Academy of Medical Sciences Oxford Institute (CAMS Oxford Institute), University of Oxford, Oxford, United Kingdom
- Rouzheng Wang
- Third Affiliated Hospital, Xinjiang Tumor Hospital, Xinjiang Medical University, Ürümqi, China
- Peiwen Fan
- Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Chinese Academy of Medical Sciences (CAMS), Xinjiang Medical University, Ürümqi, China
- Peiwen Fan
- Third Affiliated Hospital, Xinjiang Tumor Hospital, Xinjiang Medical University, Ürümqi, China
- Xuan Yao
- Nuffield Department of Medicine (NDM), Chinese Academy of Medical Sciences Oxford Institute (CAMS Oxford Institute), University of Oxford, Oxford, United Kingdom
- Xuan Yao
- MRC Human Immunology Unit, Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Ling Qin
- Beijing You'an Hospital, Capital Medical University, Beijing, China
- Yanchun Peng
- Nuffield Department of Medicine (NDM), Chinese Academy of Medical Sciences Oxford Institute (CAMS Oxford Institute), University of Oxford, Oxford, United Kingdom
- Yanchun Peng
- MRC Human Immunology Unit, Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Miaomiao Ma
- Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Chinese Academy of Medical Sciences (CAMS), Xinjiang Medical University, Ürümqi, China
- Miaomiao Ma
- Third Affiliated Hospital, Xinjiang Tumor Hospital, Xinjiang Medical University, Ürümqi, China
- Neil Asley
- Single Cell Genomics Facility, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Xuimei Chang
- Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Chinese Academy of Medical Sciences (CAMS), Xinjiang Medical University, Ürümqi, China
- Xuimei Chang
- Third Affiliated Hospital, Xinjiang Tumor Hospital, Xinjiang Medical University, Ürümqi, China
- Yaning Feng
- Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Chinese Academy of Medical Sciences (CAMS), Xinjiang Medical University, Ürümqi, China
- Yaning Feng
- Third Affiliated Hospital, Xinjiang Tumor Hospital, Xinjiang Medical University, Ürümqi, China
- Yunhui Hu
- Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Chinese Academy of Medical Sciences (CAMS), Xinjiang Medical University, Ürümqi, China
- Yunhui Hu
- Third Affiliated Hospital, Xinjiang Tumor Hospital, Xinjiang Medical University, Ürümqi, China
- Yonghong Zhang
- Beijing You'an Hospital, Capital Medical University, Beijing, China
- Chris Li
- China R&D, Janssen Pharmaceuticals, Shanghai, China
- Gregory Fanning
- China R&D, Janssen Pharmaceuticals, Shanghai, China
- Stephanie Jones
- Oxford Radcliffe Biobank, Department of Cellular Pathology, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
- Clare Verrill
- Nuffield Department of Surgical Sciences, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
- David Maldonado-Perez
- Nuffield Department of Surgical Sciences, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
- Paul Sopp
- 0Flow Cytometry Facility, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Craig Waugh
- 0Flow Cytometry Facility, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Stephen Taylor
- 1Bioinformatics Team, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Simon Mcgowan
- 1Bioinformatics Team, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Vincenzo Cerundolo
- Nuffield Department of Medicine (NDM), Chinese Academy of Medical Sciences Oxford Institute (CAMS Oxford Institute), University of Oxford, Oxford, United Kingdom
- Vincenzo Cerundolo
- MRC Human Immunology Unit, Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Christopher Conlon
- Nuffield Department of Medicine (NDM), Chinese Academy of Medical Sciences Oxford Institute (CAMS Oxford Institute), University of Oxford, Oxford, United Kingdom
- Andrew McMichael
- Nuffield Department of Medicine (NDM), Chinese Academy of Medical Sciences Oxford Institute (CAMS Oxford Institute), University of Oxford, Oxford, United Kingdom
- Shichun Lu
- 2China Military General Hospital, Beijing, China
- Xiyan Wang
- Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Chinese Academy of Medical Sciences (CAMS), Xinjiang Medical University, Ürümqi, China
- Xiyan Wang
- Third Affiliated Hospital, Xinjiang Tumor Hospital, Xinjiang Medical University, Ürümqi, China
- Ning Li
- Beijing You'an Hospital, Capital Medical University, Beijing, China
- Tao Dong
- Nuffield Department of Medicine (NDM), Chinese Academy of Medical Sciences Oxford Institute (CAMS Oxford Institute), University of Oxford, Oxford, United Kingdom
- Tao Dong
- MRC Human Immunology Unit, Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- DOI
- https://doi.org/10.3389/fonc.2019.01066
- Journal volume & issue
-
Vol. 9
Abstract
Background: Cancer patients often display dysfunctional antitumor T-cell responses. Because noteworthy benefits of immune checkpoint pathway blockade, such as programmed cell death protein 1 (PD-1) inhibitors, have been achieved in multiple advanced cancers, the next critical question is which mono-blockade or combinatorial blockade regimens may reinvigorate antitumor T-cell immunity in those cancer patients while limiting immune-related adverse effects.Method: This study recruited, in total, 172 primary cancer patients (131 were blood-tumor-matched patients) who were treatment-naïve prior to the surgeries or biopsies covering the eight most prevalent types of cancer. With access to fresh surgical samples, this study simultaneously investigated the ex vivo expression level of eight known immune checkpoint receptors [PD-1, cytotoxic T-lymphocyte antigen-4 [CTLA-4], T-cell immunoglobulin and mucin-domain containing-3 [Tim-3], 2B4, killer cell lectin like receptor G1 [KLRG-1], TIGIT, B- and T-lymphocyte attenuator [BTLA], and CD160] on tumor-infiltrating T cells (TILs) and paired circulating T cells in blood from a 131-patient cohort.Results: We found increased an expression of PD-1 and Tim-3 but a decreased expression of BTLA on TILs when compared with peripheral blood from multiple types of cancer. Moreover, our co-expression analysis of key immune checkpoint receptors delineates “shared” subsets as PD-1+Tim-3+TIGIT+2B4+KLRG-1–CTLA-4– and PD-1+TIGIT+2B4+Tim-3–KLRG-1–CTLA-4– from bulk CD8 TILs. Furthermore, we found that a higher frequency of advanced differentiation stage T cells (CD27–CCR7–CD45RA–) among the “shared” subset (PD-1+Tim-3+TIGIT+2B4+KLRG-1–CTLA-4–) in bulk CD8 TILs was associated with poorly differentiated cancer type in cervical cancer patients.Conclusions: To our knowledge, our study is the first comprehensive analysis of key immune checkpoint receptors on T cells in treatment-naïve, primary cancer patients from the eight most prevalent types of cancer. These findings might provide useful information for future design of mono-blockade/combinatorial blockades and/or genetically modified T-cell immunotherapy.
Keywords
- T cells
- inhibitory receptor
- tumor-infiltrating lymphocytes
- tumor microenvironment
- combinatorial checkpoint blockade
