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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 the TCR or NKG2D 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 the γδ TCR, CD3, NKG2D, or in the presence of mevastatin. Specific cytotoxicity levels achieved by the Vγ9Vδ2 T cell line COLD2-1 were 65±11 for CIC#3 and 71±9 for CIC#5. Data are mean ± SD of two experiments carried out in triplicate. Percent inhibition with anti-NKG2D mAb was significantly different than values in all other groups (*p<0.001).
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pone-0065145-g005: Modulation of the cytotoxic activity of Vγ9Vδ2 T cells by blocking the TCR or NKG2D 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 the γδ TCR, CD3, NKG2D, or in the presence of mevastatin. Specific cytotoxicity levels achieved by the Vγ9Vδ2 T cell line COLD2-1 were 65±11 for CIC#3 and 71±9 for CIC#5. Data are mean ± SD of two experiments carried out in triplicate. Percent inhibition with anti-NKG2D mAb was significantly different than values in all other groups (*p<0.001).

Mentions: Vγ9Vδ2T cells exploit different pathways for killing of tumor cells that rely on secretion of proinflammatory cytokines and proapoptotic molecules or on cell contact-dependent lysis through NK-like or TCR-dependent interactions [9]. We assessed the mechanisms responsible for killing of chemotherapy-sensitized CICs by Vγ9Vδ2T cells, by individually blocking TCR or NKG2D receptors. Cytotoxicity of chemotherapy-pretreated colon CIC lines by two different Vγ9Vδ2T cell lines was significantly inhibited by anti-NKG2D mAb, while the Vγ9Vδ2TCR seems to play a minor role as indicated by the failure of anti-CD3 and anti-pan γδ TCR mAbs to inhibit cytotoxicity (Figure 5). In addition, Vγ9Vδ2T cell killing of chemotherapy-sensitized targets was assessed in the presence of mevastatin, which inhibits 3-hydroxy-3-methylglutaryl-CoA and prevents zoledronate-mediated accumulation of endogenous phosphoantigens as IPP. Mevastatin failed to inhibit killing of all tested chemotherapy-pretreated colon CIC lines by two different allogeneic Vγ9Vδ2T cell lines (Figure 5), thus indicating that chemotherapy-induced sensitization of CICs to Vγ9Vδ2T cell cytotoxicity does not rely on production of mevalonate metabolites.


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 the TCR or NKG2D 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 the γδ TCR, CD3, NKG2D, or in the presence of mevastatin. Specific cytotoxicity levels achieved by the Vγ9Vδ2 T cell line COLD2-1 were 65±11 for CIC#3 and 71±9 for CIC#5. Data are mean ± SD of two experiments carried out in triplicate. Percent inhibition with anti-NKG2D mAb was 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-g005: Modulation of the cytotoxic activity of Vγ9Vδ2 T cells by blocking the TCR or NKG2D 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 the γδ TCR, CD3, NKG2D, or in the presence of mevastatin. Specific cytotoxicity levels achieved by the Vγ9Vδ2 T cell line COLD2-1 were 65±11 for CIC#3 and 71±9 for CIC#5. Data are mean ± SD of two experiments carried out in triplicate. Percent inhibition with anti-NKG2D mAb was significantly different than values in all other groups (*p<0.001).
Mentions: Vγ9Vδ2T cells exploit different pathways for killing of tumor cells that rely on secretion of proinflammatory cytokines and proapoptotic molecules or on cell contact-dependent lysis through NK-like or TCR-dependent interactions [9]. We assessed the mechanisms responsible for killing of chemotherapy-sensitized CICs by Vγ9Vδ2T cells, by individually blocking TCR or NKG2D receptors. Cytotoxicity of chemotherapy-pretreated colon CIC lines by two different Vγ9Vδ2T cell lines was significantly inhibited by anti-NKG2D mAb, while the Vγ9Vδ2TCR seems to play a minor role as indicated by the failure of anti-CD3 and anti-pan γδ TCR mAbs to inhibit cytotoxicity (Figure 5). In addition, Vγ9Vδ2T cell killing of chemotherapy-sensitized targets was assessed in the presence of mevastatin, which inhibits 3-hydroxy-3-methylglutaryl-CoA and prevents zoledronate-mediated accumulation of endogenous phosphoantigens as IPP. Mevastatin failed to inhibit killing of all tested chemotherapy-pretreated colon CIC lines by two different allogeneic Vγ9Vδ2T cell lines (Figure 5), thus indicating that chemotherapy-induced sensitization of CICs to Vγ9Vδ2T cell cytotoxicity does not rely on production of mevalonate metabolites.

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