Research Papers:

Profiling the dynamic expression of checkpoint molecules on cytokine-induced killer cells from non-small-cell lung cancer patients

Lin Zhang, Jian Wang, Feng Wei, Kaiyuan Wang, Qian Sun, Fan Yang, Hao Jin, Yu Zheng, Hua Zhao, Limei Wang, Wenwen Yu, Xiying Zhang, Yang An, Lili Yang, Xinwei Zhang and Xiubao Ren _

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Oncotarget. 2016; 7:43604-43615. https://doi.org/10.18632/oncotarget.9871

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Lin Zhang1,3,4,*, Jian Wang1,3,4,*, Feng Wei1,3,4, Kaiyuan Wang1,3,4, Qian Sun1,3,4, Fan Yang2,3,4, Hao Jin1,3,4, Yu Zheng2,3,4, Hua Zhao1,3,4, Limei Wang1,3,4, Wenwen Yu1,3,4, Xiying Zhang1,3,4, Yang An1,3,4, Lili Yang1,3,4, Xinwei Zhang2,3,4, Xiubao Ren2,3,4

1Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tiyuanbei, Tianjin, China

2Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

3National Clinical Research Center of Cancer, Tianjin, China

4Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China

*These authors contributed equally to this work as co-first authors

Correspondence to:

Xiubao Ren, email: renxiubao@tjmuch.com

Keywords: checkpoint molecule, cytokine-induced killer cell (CIK), non-small-cell lung cancer (NSCLC), immunotherapy

Received: January 19, 2016     Accepted: May 12, 2016     Published: June 07, 2016


Immune checkpoints associate with dysfunctional T cells, which have a reduced ability to clear pathogens or cancer cells. T-cell checkpoint blockade may improve patient survival. However, checkpoint molecules on cytokine-induced killer (CIK) cell, a non-specific adoptive immunotherapy, remain unknown. In present study, we detected the dynamic expression of eight major checkpoint molecules (CTLA-4, PD-1, PD-L1, TIM-3, CEACAM-1, LAG-3, TIGIT and BTLA) on CIK cells from NSCLC patients. The majority of these molecules, except BTLA, were sharply elevated during the early stage of CIK cell culture. Thereafter, PD-1 and TIGIT expressions decreased gradually towards the initial level (day 0). Moreover, CTLA-4 faded away during the later stage of CIK culture. LAG-3 expression decreased but was still significantly higher than the initial level. Of note, PD-L1 remained stably upregulated during CIK culture compared with PD-1, indicating that PD-L1 might act as an inhibitory molecule on CIK cells instead of PD-1. Furthermore, TIM-3 and CEACAM1 were strongly expressed simultaneously during long-term CIK culture and showed a significant and mutually positive correlation. BTLA displayed a distinct pattern, and its expression gradually decreased throughout the CIK culture. These observations suggested that CIK cells might be partly exhausted before clinical transfusion, characterized by the high expression of PD-L1, LAG-3, TIM-3, and CEACAM-1 and the low expression of TIGIT, BTLA, PD-1, and CTLA-4 compared with initial culture. Our results imply that implementing combined treatment on CIK cells before transfusion via antibodies targeting PD-L1, LAG-3, TIM-3, and CEACAM-1 might improve the efficiency of CIK therapy for NSCLC patients.

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