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Cetuximab intensifies the ADCC activity of adoptive NK cells in a nude mouse colorectal cancer xenograft model

View Article: PubMed Central - PubMed

ABSTRACT

Natural killer (NK) cells, discovered ~40 years ago, are believed to be the most effective cytotoxic lymphocytes to counteract cancer; however, adoptive NK cell therapy in vivo has encountered certain limitations, including a lack of specificity. The drug cetuximab can mediate antibody dependent cell mediated cytotoxicity (ADCC) activity through NK cells in vivo, and has been approved for the first-line treatment of epidermal growth factor receptor (EGFR)-positive metastatic colorectal cancer (CRC). However, the ADCC activity of adoptive NK cells, induced by cetuximab in a nude mouse CRC xenograft model, has not been previously reported. The aim of the present study was to explore the ADCC activity of cetuximab combined with adoptive NK cells in CRC xenograft models with various EGFR expressions. The nude mouse xenograft models were established by subcutaneously injecting LOVO or SW620 cells. The mice were then randomly divided into 6 groups: Phosphate-buffered saline, cetuximab, human immunoglobulin G (hIgG), NK cells, hIgG plus NK cells and cetuximab plus NK cells. The ADCC antitumor activity was evaluated in these CRC models. The results indicated that the cetuximab plus NK cells group showed the greatest tumor inhibition effect compared with the NK cells group in LOVO xenograft tumor models with positive EGFR expression. However, the combination of cetuximab and NK cells did not show a stronger tumor inhibitory effect against the SW620 xenograft tumor models compared with the efficiency of NK cells. In conclusion, cetuximab could intensify the ADCC antitumor activity of adoptive NK cells towards CRC with an increased EGFR expression. The combination of cetuximab and NK cells may be a potential immunotherapy for metastatic CRC patients with positive EGFR expression.

No MeSH data available.


Apotosis in LOVO xenograft tissues by terminal deoxynucleotidyl transferase dUTP nick end labeling. Original magnification, ×200. (A) Phosphate-buffered saline group. (B) hIgG group. (C) Cetuximab group. (D) NK cells group. (E) hIgG+NK cells group. (F) Cetuximab+NK cells group. hIgG, human immunoglobulin G; NK, natural killer.
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f7-ol-0-0-4835: Apotosis in LOVO xenograft tissues by terminal deoxynucleotidyl transferase dUTP nick end labeling. Original magnification, ×200. (A) Phosphate-buffered saline group. (B) hIgG group. (C) Cetuximab group. (D) NK cells group. (E) hIgG+NK cells group. (F) Cetuximab+NK cells group. hIgG, human immunoglobulin G; NK, natural killer.

Mentions: TUNEL assays are an indicator of cell apoptosis, in which the nuclei are stained brown in positively staining cells. The results showed that the AI of the LOVO xenograft tumors was 73.80±4.35% in the cetuximab combined with NK cells group, which was evidently increased compared with other groups (P<0.0001 compared with the PBS group, P<0.0001 compared with the hIgG group, P=0.008 compared with the cetuximab group, P=0.008 compared with the NK cells group and P=0.002 compared with the hIgG plus NK cells group). The AI in the cetuximab, NK cells and NK cells plus hIgG groups increased compared with the PBS control group (P=0.0009, P=0.0009 and P=0.0003, respectively). The AI of the SW620 xenograft tumors in the cetuximab combined with NK cells, the NK cells and the NK cells plus hIgG groups were increased compared with the PBS control group (P=0.018, P=0.004 and P=0.0007, respectively); however no significant difference was identified between the 3 (non-control) groups (P=0.533). The AI in the cetuximab group was similar to the control group (P=0.780). These results suggest that NK cells may promote LOVO xenograft tumor cell apoptosis in vivo, and that the effects are increased by the participation of cetuximab. However, SW620 xenograft tumor cell apoptosis was not influenced by cetuximab (Figs. 7 and 8; Table IV).


Cetuximab intensifies the ADCC activity of adoptive NK cells in a nude mouse colorectal cancer xenograft model
Apotosis in LOVO xenograft tissues by terminal deoxynucleotidyl transferase dUTP nick end labeling. Original magnification, ×200. (A) Phosphate-buffered saline group. (B) hIgG group. (C) Cetuximab group. (D) NK cells group. (E) hIgG+NK cells group. (F) Cetuximab+NK cells group. hIgG, human immunoglobulin G; NK, natural killer.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4998150&req=5

f7-ol-0-0-4835: Apotosis in LOVO xenograft tissues by terminal deoxynucleotidyl transferase dUTP nick end labeling. Original magnification, ×200. (A) Phosphate-buffered saline group. (B) hIgG group. (C) Cetuximab group. (D) NK cells group. (E) hIgG+NK cells group. (F) Cetuximab+NK cells group. hIgG, human immunoglobulin G; NK, natural killer.
Mentions: TUNEL assays are an indicator of cell apoptosis, in which the nuclei are stained brown in positively staining cells. The results showed that the AI of the LOVO xenograft tumors was 73.80±4.35% in the cetuximab combined with NK cells group, which was evidently increased compared with other groups (P<0.0001 compared with the PBS group, P<0.0001 compared with the hIgG group, P=0.008 compared with the cetuximab group, P=0.008 compared with the NK cells group and P=0.002 compared with the hIgG plus NK cells group). The AI in the cetuximab, NK cells and NK cells plus hIgG groups increased compared with the PBS control group (P=0.0009, P=0.0009 and P=0.0003, respectively). The AI of the SW620 xenograft tumors in the cetuximab combined with NK cells, the NK cells and the NK cells plus hIgG groups were increased compared with the PBS control group (P=0.018, P=0.004 and P=0.0007, respectively); however no significant difference was identified between the 3 (non-control) groups (P=0.533). The AI in the cetuximab group was similar to the control group (P=0.780). These results suggest that NK cells may promote LOVO xenograft tumor cell apoptosis in vivo, and that the effects are increased by the participation of cetuximab. However, SW620 xenograft tumor cell apoptosis was not influenced by cetuximab (Figs. 7 and 8; Table IV).

View Article: PubMed Central - PubMed

ABSTRACT

Natural killer (NK) cells, discovered ~40 years ago, are believed to be the most effective cytotoxic lymphocytes to counteract cancer; however, adoptive NK cell therapy in vivo has encountered certain limitations, including a lack of specificity. The drug cetuximab can mediate antibody dependent cell mediated cytotoxicity (ADCC) activity through NK cells in vivo, and has been approved for the first-line treatment of epidermal growth factor receptor (EGFR)-positive metastatic colorectal cancer (CRC). However, the ADCC activity of adoptive NK cells, induced by cetuximab in a nude mouse CRC xenograft model, has not been previously reported. The aim of the present study was to explore the ADCC activity of cetuximab combined with adoptive NK cells in CRC xenograft models with various EGFR expressions. The nude mouse xenograft models were established by subcutaneously injecting LOVO or SW620 cells. The mice were then randomly divided into 6 groups: Phosphate-buffered saline, cetuximab, human immunoglobulin G (hIgG), NK cells, hIgG plus NK cells and cetuximab plus NK cells. The ADCC antitumor activity was evaluated in these CRC models. The results indicated that the cetuximab plus NK cells group showed the greatest tumor inhibition effect compared with the NK cells group in LOVO xenograft tumor models with positive EGFR expression. However, the combination of cetuximab and NK cells did not show a stronger tumor inhibitory effect against the SW620 xenograft tumor models compared with the efficiency of NK cells. In conclusion, cetuximab could intensify the ADCC antitumor activity of adoptive NK cells towards CRC with an increased EGFR expression. The combination of cetuximab and NK cells may be a potential immunotherapy for metastatic CRC patients with positive EGFR expression.

No MeSH data available.