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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.


Expression of Ki-67 in SW620 xenograft tissues by immunohistochemistry. 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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f6-ol-0-0-4835: Expression of Ki-67 in SW620 xenograft tissues by immunohistochemistry. 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: Ki-67 is an indicator of cell proliferation and is mainly expressed in the cell nucleus. IHC staining showed that the Ki-67 expression of LOVO xenograft tumors in the cetuximab plus NK cells group was 23.8±3.89%, which was decreased compared with the NK cells and cetuximab groups (P=0.003 and P=0.002, respectively). The expression of Ki-67 in the cetuximab plus NK cells group was weak positive (+), whereas the expression in the control groups (PBS and hIgG) was strong positive (+++). In the SW620 xenograft tumor models, the Ki-67 expression in the cetuximab plus NK cells group was not decreased compared with the NK cells group (P=0.173). In addition, the Ki-67 expression in the cetuximab group also showed no significant difference compared with the control group (P=0.862). These results indicate that cetuximab or adoptive NK cells may inhibit the proliferation of tumor cells in LOVO xenografts, and that the combination of cetuximab and NK cells significantly improved this effect. Nevertheless, cell proliferation remained active and was not affected by cetuximab in the SW620 cell xenograft tumors (Figs. 5 and 6; Table III).


Cetuximab intensifies the ADCC activity of adoptive NK cells in a nude mouse colorectal cancer xenograft model
Expression of Ki-67 in SW620 xenograft tissues by immunohistochemistry. 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

f6-ol-0-0-4835: Expression of Ki-67 in SW620 xenograft tissues by immunohistochemistry. 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: Ki-67 is an indicator of cell proliferation and is mainly expressed in the cell nucleus. IHC staining showed that the Ki-67 expression of LOVO xenograft tumors in the cetuximab plus NK cells group was 23.8±3.89%, which was decreased compared with the NK cells and cetuximab groups (P=0.003 and P=0.002, respectively). The expression of Ki-67 in the cetuximab plus NK cells group was weak positive (+), whereas the expression in the control groups (PBS and hIgG) was strong positive (+++). In the SW620 xenograft tumor models, the Ki-67 expression in the cetuximab plus NK cells group was not decreased compared with the NK cells group (P=0.173). In addition, the Ki-67 expression in the cetuximab group also showed no significant difference compared with the control group (P=0.862). These results indicate that cetuximab or adoptive NK cells may inhibit the proliferation of tumor cells in LOVO xenografts, and that the combination of cetuximab and NK cells significantly improved this effect. Nevertheless, cell proliferation remained active and was not affected by cetuximab in the SW620 cell xenograft tumors (Figs. 5 and 6; Table III).

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.