2019•Frontiers in OncologyOpen access
A Comprehensive Analysis of Key Immune Checkpoint Receptors on Tumor-Infiltrating T Cells From Multiple Types of Cancer
Xi Li, Rouzheng Wang, Peiwen Fan, Xuan Yao, Ling Qin, Yanchun Peng, Miaomiao Ma, Neil Asley, Xuimei Chang, Yaning Feng, Yunhui Hu, Yonghong Zhang, Chris Li, Gregory C. Fanning, Stephanie Jones, Clare L. Verrill, David Maldonado‐Pérez, Paul Sopp, Craig Waugh, Stephen Taylor, Simon J. McGowan, Vincenzo Cerundolo, Christopher P. Conlon, Andrew McMichael, Shichun Lu, Xiyan Wang, Ning Li, Tao Dong
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Abstract
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.
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