Targeting CD155 by rediocide-A overcomes tumour immuno-resistance to natural killer cells

Abstract

Context

Therapeutic benefits of immunotherapy are restricted by cancer immune-resistance mechanisms. Rediocide-A (Red-A), a natural product extracted from Traditional Chinese Medicine, is a promising agent to battle against cancer which acts as an immune checkpoint inhibitor.

Objective

To investigate the effect of Red-A on NK-cell tumouricidal activity.

Materials and methods

NK cells were co-cultured with A549 or H1299 cells and treated with 10 or 100 nM Red-A for 24 h. Cells treated with 0.1% dimethyl sulphoxide (DMSO) was employed as vehicle control. NK cell-mediated cytotoxicity was detected by biophotonic cytotoxicity and impedance assay. Degranulation, granzyme B, NK cell-tumour cell conjugates and ligands profiling were detected by flow cytometry. Interferon-γ (IFN- γ) production was assessed by enzyme-linked immunosorbent assay (ELISA).

Results

Red-A increased NK cell-mediated lysis of A549 cells by 3.58-fold (21.86% vs. 78.27%) and H1299 cells by 1.26-fold (59.18% vs. 74.78%), compared to vehicle control. Granzyme B level was increased by 48.01% (A549 cells) and 53.26% (H1299 cells) after 100 nM Red-A treatment. INF-γ level was increased by 3.23-fold (A549 cells) and 6.77-fold (H1299 cells) after 100 nM Red-A treatment. Red-A treatment down-regulated the expression level of CD155 by 14.41% and 11.66% in A549 cells and H1299 cells, respectively, leading to the blockade of tumour immuno-resistance to NK cells.

Conclusions

Red-A overcomes immuno-resistance of NSCLCs to NK cells by down-regulating CD155 expression, which shows the possibility of developing checkpoint inhibitors targeting TIGIT/CD155 signalling to overcome immuno-resistance of cancer cells.

Keywords:

• Cancer immunotherapy
• high-throughput assay
• immune checkpoint
• natural products
• non-small cell lung cancer

Author contributions

WN performed the experiments and wrote the manuscript. CG, XY, GS, CF, LW, ZX, XZ participated in the experiments. CY and SZ conceived the study, participated in its design and coordination. All authors read and approved the final manuscript.

Disclosure statement

The authors declare that they are no conflict of interest.

Additional information

Funding

This study was supported by National Natural Science Foundation of China [No. 81903848 and 81473237]; Shanghai Sailing Program [No. 19YF1448700]; and China Postdoctoral Science Foundation Grant [No. 2018M642062].