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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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Modulation of the cytotoxic activity of Vγ9Vδ2 T cells by blocking death receptors interactions.The Vγ9Vδ2 T cell line COLD2-1 was cultured with two chemotherapy-treated colon CICs (CIC#3 and CIC#5) at an E:T ratio of 20∶1, in the presence of blocking antibodies to TNF-α, FasL (CD95L), TRAIL receptors R1 (DR4) or R2 (DR5), or concanamycin A (CMA). Specific cytotoxicity levels achieved by the Vγ9Vδ2 T cell line COLD2-1 were 61±7 for CIC#3 and 65±12 for CIC#5. Data are mean ± SD of experiments carried out in triplicate. Percent inhibition with anti-DR5 and anti-TRAIL mAbs were significantly different than values in all other groups (*p<0.001).
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pone-0065145-g006: Modulation of the cytotoxic activity of Vγ9Vδ2 T cells by blocking death receptors interactions.The Vγ9Vδ2 T cell line COLD2-1 was cultured with two chemotherapy-treated colon CICs (CIC#3 and CIC#5) at an E:T ratio of 20∶1, in the presence of blocking antibodies to TNF-α, FasL (CD95L), TRAIL receptors R1 (DR4) or R2 (DR5), or concanamycin A (CMA). Specific cytotoxicity levels achieved by the Vγ9Vδ2 T cell line COLD2-1 were 61±7 for CIC#3 and 65±12 for CIC#5. Data are mean ± SD of experiments carried out in triplicate. Percent inhibition with anti-DR5 and anti-TRAIL mAbs were significantly different than values in all other groups (*p<0.001).

Mentions: To further elucidate the mechanisms of killing of chemotherapy-sensitized colon CICs by Vγ9Vδ2T cells, we individually inhibited the granule exocytosis, TNF-α-, TRAIL-, and FasL-mediated pathways. Killing-inhibition experiments revealed that Vγ9Vδ2T cell cytotoxicity of chemotherapy-pretreated colon CIC targets was significantly inhibited by anti-DR5 mAb, whereas mAbs against DR4, TNF-α, and FasL, or treatment with CMA to block the granule-exocytosis pathway, all failed to inhibit. Figure 6 shows representative data with two Vγ9Vδ2T cell lines and the two colon CIC lines, CIC#2 and CIC#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)

Modulation of the cytotoxic activity of Vγ9Vδ2 T cells by blocking death receptors interactions.The Vγ9Vδ2 T cell line COLD2-1 was cultured with two chemotherapy-treated colon CICs (CIC#3 and CIC#5) at an E:T ratio of 20∶1, in the presence of blocking antibodies to TNF-α, FasL (CD95L), TRAIL receptors R1 (DR4) or R2 (DR5), or concanamycin A (CMA). Specific cytotoxicity levels achieved by the Vγ9Vδ2 T cell line COLD2-1 were 61±7 for CIC#3 and 65±12 for CIC#5. Data are mean ± SD of experiments carried out in triplicate. Percent inhibition with anti-DR5 and anti-TRAIL mAbs were significantly different than values in all other groups (*p<0.001).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0065145-g006: Modulation of the cytotoxic activity of Vγ9Vδ2 T cells by blocking death receptors interactions.The Vγ9Vδ2 T cell line COLD2-1 was cultured with two chemotherapy-treated colon CICs (CIC#3 and CIC#5) at an E:T ratio of 20∶1, in the presence of blocking antibodies to TNF-α, FasL (CD95L), TRAIL receptors R1 (DR4) or R2 (DR5), or concanamycin A (CMA). Specific cytotoxicity levels achieved by the Vγ9Vδ2 T cell line COLD2-1 were 61±7 for CIC#3 and 65±12 for CIC#5. Data are mean ± SD of experiments carried out in triplicate. Percent inhibition with anti-DR5 and anti-TRAIL mAbs were significantly different than values in all other groups (*p<0.001).
Mentions: To further elucidate the mechanisms of killing of chemotherapy-sensitized colon CICs by Vγ9Vδ2T cells, we individually inhibited the granule exocytosis, TNF-α-, TRAIL-, and FasL-mediated pathways. Killing-inhibition experiments revealed that Vγ9Vδ2T cell cytotoxicity of chemotherapy-pretreated colon CIC targets was significantly inhibited by anti-DR5 mAb, whereas mAbs against DR4, TNF-α, and FasL, or treatment with CMA to block the granule-exocytosis pathway, all failed to inhibit. Figure 6 shows representative data with two Vγ9Vδ2T cell lines and the two colon CIC lines, CIC#2 and CIC#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