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Chemotherapy sensitizes colon cancer initiating cells to Vγ9Vδ2 T cell-mediated cytotoxicity.

Todaro M, Orlando V, Cicero G, Caccamo N, Meraviglia S, Stassi G, Dieli F - PLoS ONE (2013)

Bottom Line: Combinations of immune-based therapies with chemotherapy and other anti-tumor agents may be of significant clinical benefit in the treatment of colon cancer.Vγ9Vδ2 T cell cytotoxicity was largely mediated by TRAIL interaction with DR5, following NKG2D-dependent recognition of colon CIC targets.We conclude that in vivo activation of Vγ9Vδ2 T cells or adoptive administration of ex-vivo expanded Vγ9Vδ2 T cells at suitable intervals after chemotherapy may substantially increase anti-tumor activities and represent a novel strategy for colon cancer immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Discipline Chirurgiche ed Anatomiche, Università di Palermo, Palermo, Italy.

ABSTRACT
Colon cancer comprises a small population of cancer initiating stem cells (CIC) that is responsible for tumor maintenance and resistance to anti-cancer therapies, possibly allowing for tumor recapitulation once treatment stops. Combinations of immune-based therapies with chemotherapy and other anti-tumor agents may be of significant clinical benefit in the treatment of colon cancer. However, cellular immune-based therapies have not been experimented yet in the population of colon CICs. Here, we demonstrate that treatment with low concentrations of commonly used chemotherapeutic agents, 5-fluorouracyl and doxorubicin, sensitize colon CICs to Vγ9Vδ2 T cell cytotoxicity. Vγ9Vδ2 T cell cytotoxicity was largely mediated by TRAIL interaction with DR5, following NKG2D-dependent recognition of colon CIC targets. We conclude that in vivo activation of Vγ9Vδ2 T cells or adoptive administration of ex-vivo expanded Vγ9Vδ2 T cells at suitable intervals after chemotherapy may substantially increase anti-tumor activities and represent a novel strategy for colon cancer immunotherapy.

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Chemotherapy upregulates DR5 expression on coloc CICs.Colon CICs were treated with medium, 5-FU (25 µg/ml) or DXR (0.25 µM) for 48 hrs, washed extensively and stained with anti-DR5 mAb. Flow cytometry histograms show DR5. Mean fluorescence intensity (MFI) for DR5 staining is indicated in the upper right corner of each panel. Dotted lines represent isotype control mAb, while grey filled histogram represent anti-DR5 mAb.
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pone-0065145-g004: Chemotherapy upregulates DR5 expression on coloc CICs.Colon CICs were treated with medium, 5-FU (25 µg/ml) or DXR (0.25 µM) for 48 hrs, washed extensively and stained with anti-DR5 mAb. Flow cytometry histograms show DR5. Mean fluorescence intensity (MFI) for DR5 staining is indicated in the upper right corner of each panel. Dotted lines represent isotype control mAb, while grey filled histogram represent anti-DR5 mAb.

Mentions: Expression of Fas (CD95), TNF-R1, DR4 (TRAIL-R1) and DR5 (TRAIL-R2) death receptors was increased in the majority of CIC lines following exposure to chemotherapeutic agents (Figure 3), but increased expression of Fas, TNF-R1 and DR4 did not attain statistical significance. The greatest and significant increase was only observed for DR5 expression after exposure of CICs to 5-FU and, although at a lesser extent, DXR (Figure 3). Upregulation of DR5 following 48 hrs exposure of colon CICs to chemotherapy was confirmed by flow cytometry upon staining with specific mAb (Figure 4).


Chemotherapy sensitizes colon cancer initiating cells to Vγ9Vδ2 T cell-mediated cytotoxicity.

Todaro M, Orlando V, Cicero G, Caccamo N, Meraviglia S, Stassi G, Dieli F - PLoS ONE (2013)

Chemotherapy upregulates DR5 expression on coloc CICs.Colon CICs were treated with medium, 5-FU (25 µg/ml) or DXR (0.25 µM) for 48 hrs, washed extensively and stained with anti-DR5 mAb. Flow cytometry histograms show DR5. Mean fluorescence intensity (MFI) for DR5 staining is indicated in the upper right corner of each panel. Dotted lines represent isotype control mAb, while grey filled histogram represent anti-DR5 mAb.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675136&req=5

pone-0065145-g004: Chemotherapy upregulates DR5 expression on coloc CICs.Colon CICs were treated with medium, 5-FU (25 µg/ml) or DXR (0.25 µM) for 48 hrs, washed extensively and stained with anti-DR5 mAb. Flow cytometry histograms show DR5. Mean fluorescence intensity (MFI) for DR5 staining is indicated in the upper right corner of each panel. Dotted lines represent isotype control mAb, while grey filled histogram represent anti-DR5 mAb.
Mentions: Expression of Fas (CD95), TNF-R1, DR4 (TRAIL-R1) and DR5 (TRAIL-R2) death receptors was increased in the majority of CIC lines following exposure to chemotherapeutic agents (Figure 3), but increased expression of Fas, TNF-R1 and DR4 did not attain statistical significance. The greatest and significant increase was only observed for DR5 expression after exposure of CICs to 5-FU and, although at a lesser extent, DXR (Figure 3). Upregulation of DR5 following 48 hrs exposure of colon CICs to chemotherapy was confirmed by flow cytometry upon staining with specific mAb (Figure 4).

Bottom Line: Combinations of immune-based therapies with chemotherapy and other anti-tumor agents may be of significant clinical benefit in the treatment of colon cancer.Vγ9Vδ2 T cell cytotoxicity was largely mediated by TRAIL interaction with DR5, following NKG2D-dependent recognition of colon CIC targets.We conclude that in vivo activation of Vγ9Vδ2 T cells or adoptive administration of ex-vivo expanded Vγ9Vδ2 T cells at suitable intervals after chemotherapy may substantially increase anti-tumor activities and represent a novel strategy for colon cancer immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Discipline Chirurgiche ed Anatomiche, Università di Palermo, Palermo, Italy.

ABSTRACT
Colon cancer comprises a small population of cancer initiating stem cells (CIC) that is responsible for tumor maintenance and resistance to anti-cancer therapies, possibly allowing for tumor recapitulation once treatment stops. Combinations of immune-based therapies with chemotherapy and other anti-tumor agents may be of significant clinical benefit in the treatment of colon cancer. However, cellular immune-based therapies have not been experimented yet in the population of colon CICs. Here, we demonstrate that treatment with low concentrations of commonly used chemotherapeutic agents, 5-fluorouracyl and doxorubicin, sensitize colon CICs to Vγ9Vδ2 T cell cytotoxicity. Vγ9Vδ2 T cell cytotoxicity was largely mediated by TRAIL interaction with DR5, following NKG2D-dependent recognition of colon CIC targets. We conclude that in vivo activation of Vγ9Vδ2 T cells or adoptive administration of ex-vivo expanded Vγ9Vδ2 T cells at suitable intervals after chemotherapy may substantially increase anti-tumor activities and represent a novel strategy for colon cancer immunotherapy.

Show MeSH
Related in: MedlinePlus