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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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Colon CICs constitutively express molecules involved in by Vγ9Vδ2 T cell-mediated cytotoxicity: effect of chemotherapy.RT-PCR of the expression of mRNA encoding for different surface molecules in colon CICs treated with or without either 5-FU (25 µg/ml) or DXR (0.25 µM) for 48 hrs. Data represent the mean values ± SD of 4 separate experiments, each performed with colon cancer spheres from 5 different patients (CIC#1 to CIC#5).
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pone-0065145-g003: Colon CICs constitutively express molecules involved in by Vγ9Vδ2 T cell-mediated cytotoxicity: effect of chemotherapy.RT-PCR of the expression of mRNA encoding for different surface molecules in colon CICs treated with or without either 5-FU (25 µg/ml) or DXR (0.25 µM) for 48 hrs. Data represent the mean values ± SD of 4 separate experiments, each performed with colon cancer spheres from 5 different patients (CIC#1 to CIC#5).

Mentions: To decipher the molecular mechanisms behind chemotherapy-mediated sensitization of CICs to Vγ9Vδ2 T cells cytotoxicity, we focused on expression of mRNA encoding for molecules known to be ligands for key activating receptors on Vγ9Vδ2 T cells and death receptors, before and after exposure of CICs to chemotherapy agents. As shown in Figure 3, all of these molecules were constitutively expressed in CICs, although expression consistently varied amongst different CIC lines; however, no major differences were observed in all tested CIC lines for HLA-class I, ICAM-1, CD155, CD112, MICA/B and ULPBP1–4 expression before and after exposure to chemotherapy agents.


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)

Colon CICs constitutively express molecules involved in by Vγ9Vδ2 T cell-mediated cytotoxicity: effect of chemotherapy.RT-PCR of the expression of mRNA encoding for different surface molecules in colon CICs treated with or without either 5-FU (25 µg/ml) or DXR (0.25 µM) for 48 hrs. Data represent the mean values ± SD of 4 separate experiments, each performed with colon cancer spheres from 5 different patients (CIC#1 to CIC#5).
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Related In: Results  -  Collection

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

pone-0065145-g003: Colon CICs constitutively express molecules involved in by Vγ9Vδ2 T cell-mediated cytotoxicity: effect of chemotherapy.RT-PCR of the expression of mRNA encoding for different surface molecules in colon CICs treated with or without either 5-FU (25 µg/ml) or DXR (0.25 µM) for 48 hrs. Data represent the mean values ± SD of 4 separate experiments, each performed with colon cancer spheres from 5 different patients (CIC#1 to CIC#5).
Mentions: To decipher the molecular mechanisms behind chemotherapy-mediated sensitization of CICs to Vγ9Vδ2 T cells cytotoxicity, we focused on expression of mRNA encoding for molecules known to be ligands for key activating receptors on Vγ9Vδ2 T cells and death receptors, before and after exposure of CICs to chemotherapy agents. As shown in Figure 3, all of these molecules were constitutively expressed in CICs, although expression consistently varied amongst different CIC lines; however, no major differences were observed in all tested CIC lines for HLA-class I, ICAM-1, CD155, CD112, MICA/B and ULPBP1–4 expression before and after exposure to chemotherapy agents.

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