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

Abstract

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.

Epidermal growth factor induces STAT1 expression to exacerbate the IFNr‐mediated PD‐L1 axis in epidermal growth factor receptor‐positive cancers

“…Immunotherapy is an effective strategy against tumors, and the therapeutic targets of immune checkpoint proteins include programmed death‐1 (PD‐1), TIGIT, LAG‐3, and TIM‐3; the inhibition of the described targets by their antibodies has the potential to reactivate immune system elements such as cytotoxic CD8+ T cells . The results of this study indicated that the overexpression of other immune checkpoints in the KOSC‐3‐derived tumorspheres (Table ), include PD‐L2 , Gal‐9 , HLA‐E , and CD155 .…”

The Immune Regulatory Role of Cytokine-Induced Killer Cells Treatment on Non-Small Cell Lung Cancer Patients

“…However, our immune system does not work effectively in the setting of malignancy. The reason for this may be the existence of immune suppression [60][61][62].…”

“…These checkpoint expressed on T-cells was found in peripheral blood and tumor tissue have limited ability to effectively eliminate tumors, have gained considerable attention and PD-1 expression on peripheral blood T-cell subsets correlates with prognosis in non-small cell lung cancer [88,89]. These molecules were found expressed on CIK cells [60]. The majority of these molecules, except BTLA were increased during CIK cells culture.…”

New PD-L1 inhibitors in non-small cell lung cancer – impact of atezolizumab

“…Recent research has led to an improved understanding of the immune system resulting in better therapeutic strategies. The initiation of the immune cascade is a multifaceted, multistep process 2–4. The major histocompatibility complex (MHC), expressed on the surface of antigen-presenting cells (APCs), assists with internalizing and identifying tumor antigens.…”