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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01066

A comprehensive analysis of key immune checkpoint receptors on tumor infiltrating T cells from multiple types of cancer

 Xi Li1, Ruozheng Wang2,  Peiwen Fan2, Xuan Yao3,  Ling Qin4,  Yanchun Peng3, Miaomiao Ma2, Neil Ashley3, Xuemei Chang2, Yaning Feng2, Yunhui Hu2,  Yonghong Zhang4,  Chris Li5, Gregory Fanning5,  Stephanie Jones6, Clare Verill7, David Maldonado-Perez6, Paul Sopp3, Craig Waugh3,  Stephen Taylor3, Simon Mcgowan3,  Vincenzo Cerundolo3, Chris Conlon8, Andrew McMichael8, Shichun Lu9, Xiyan Wang2, Ning Li4 and  Tao Dong3, 8*
  • 1Nuffield Department of Medicine, Medical Sciences Division, University of Oxford, United Kingdom
  • 2Affiliated Tumor Hospital, Xinjiang Medical University, China
  • 3Weatherall Institute of Molecular Medicine (MRC), United Kingdom
  • 4Beijing Youan Hospital, Capital Medical University, China
  • 5Xi'an Janssen Pharmaceutical Co.,Ltd., China
  • 6Oxford Radcliffe Biobank (ORB), United Kingdom
  • 7Nuffield Department of Surgical Sciences, Medical Sciences Division, University of Oxford, United Kingdom
  • 8Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, United Kingdom
  • 9China Meitan General Hospital, China

Background: Cancer patients often display dysfunctional anti-tumor T cell responses. Since noteworthy benefits of immune checkpoint pathway blockade, such as PD-1 inhibitors, have been achieved in multiple advanced cancers, the next critical question is which mono- or combinatorial blockade regimens may reinvigorate anti-tumor 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 8 most prevalent types of cancer. With access to fresh surgical samples, this study simultaneously investigated the ex vivo expression level of 8 known immune checkpoint receptors (PD-1, CTLA-4, Tim-3, 2B4, KLRG-1, TIGIT, 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 expression of PD-1 and Tim-3 but decreased expression of BTLA on tumor-infiltrating T cells when compared to 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 higher frequency of advanced differentiation stage T cells (CD27-CCR7-CD45RA-) amongst 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 8 most prevalent types of cancer. These findings might provide useful information for future design of mono-/combinatorial blockades and/or genetically-modified T cell immunotherapy.

Keywords: T cells, Inhibitory receptors of lymphocytes, Tumor infiltrating lymphocytes (TILs), tumor microenvironment (TMA), Checkpoint blockade immunotherapy

Received: 14 May 2019; Accepted: 30 Sep 2019.

Copyright: © 2019 Li, Wang, Fan, Yao, Qin, Peng, Ma, Ashley, Chang, Feng, Hu, Zhang, Li, Fanning, Jones, Verill, Maldonado-Perez, Sopp, Waugh, Taylor, Mcgowan, Cerundolo, Conlon, McMichael, Lu, Wang, Li and Dong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Tao Dong, Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, United Kingdom, tao.dong@imm.ox.ac.uk