Cytotoxic T Cells Specifically Induce Fas on Target Cells, Thereby Facilitating Exocytosis-Independent Induction of Apoptosis

Simon, Markus M.; Waring, Paul; Lobigs, Mario; Nil, Ahmed; Tran, Thao; Hla, Ron Tha; Chin, Seow; Müllbacher, Arno

doi:10.4049/jimmunol.165.7.3663

Cited by 37 publications

(48 citation statements)

References 47 publications

(42 reference statements)

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“…This pathway of cellular cytotoxicity is thought to be primarily involved in immune regulation and maintenance of tolerance. In this context, Fas expression level is thought to be a determining factor in induction of apoptosis (46). The data presented here clearly demonstrate that C4HD tumor cells can undergo cytolysis induced by CD4 ϩ T celldepleted splenocytes, obtained from mice immunized with AS-[S]ODN-treated C4HD cells, through the Fas/FasL, but not through the perforin-dependent lytic pathway.…”

Section: Discussionmentioning

confidence: 54%

Immunization with Murine Breast Cancer Cells Treated with Antisense Oligodeoxynucleotides to Type I Insulin-Like Growth Factor Receptor Induced an Antitumoral Effect Mediated by a CD8+ Response Involving Fas/Fas Ligand Cytotoxic Pathway

Schillaci

Salatino

Cassataro

et al. 2006

The Journal of Immunology

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We have demonstrated that in vivo administration of phosphorothioate antisense oligodeoxynucleotides (AS[S]ODNs) to type I insulin-like growth factor receptor (IGF-IR) mRNA resulted in inhibition of C4HD breast cancer growth in BALB/c mice. The present study focused on whether in vivo administration of C4HD tumor cells pretreated with IGF-IR AS[S]ODN and irradiated could provide protection against C4HD wild-type tumor challenge and also on elucidating the mechanism mediating this effect. Our results showed that mice immunized with IGF-IR AS[S]ODN-treated C4HD cells experienced a growth inhibition of 53.4%, 61.6%, and 60.2% when compared with PBS-treated mice, wild-type C4HD cell-injected mice, or phosphorothioate sense oligodeoxynucleotide-treated C4HD cell-injected mice, respectively. The protective effect was C4HD-specific, because no cross-protection was observed against other syngeneic mammary tumor lines. The lack of protection against tumor formation in nude mice indicated that T cells were involved in the antitumoral response. Furthermore, cytotoxicity and splenocyte proliferation assays demonstrated that a cellular CD8+-dependent immune response, acting through the Fas/Fas ligand death pathway, could be mediating the antitumor effect induced by immunization with AS[S]ODN-treated cells. Immunization also induced splenocytes to produce Ag-dependent IFN-γ, indicating the presence of a type 1 response. We demonstrated for the first time that IGF-IR AS[S]ODN treatment of breast cancer cells induced expression of CD86 and heat shock protein 70 molecules, both involved in the induction of the immunogenic phenotype. Immunization with these tumor immunogens imparted protection against parental tumor growth through activation of a specific immune response.

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Section: Discussionmentioning

confidence: 54%

Immunization with Murine Breast Cancer Cells Treated with Antisense Oligodeoxynucleotides to Type I Insulin-Like Growth Factor Receptor Induced an Antitumoral Effect Mediated by a CD8+ Response Involving Fas/Fas Ligand Cytotoxic Pathway

Schillaci

Salatino

Cassataro

et al. 2006

The Journal of Immunology

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“…Moreover, the induction of Fas expression occurs regardless of the origin of the target cell, as both lymphoid and nonlymphoid targets up-regulate Fas when they encounter CTLs (23,24). It is likely that Fas is up-regulated in vivo at an early time point, as a recent study indicates that Fas expression is detectable as soon as 4 days after in vivo grafting (23).…”

Section: Discussionmentioning

confidence: 90%

A Central Role for Death Receptor-Mediated Apoptosis in the Rejection of Tumors by NK Cells

Screpanti

Wallin

Ljunggren

et al. 2001

The Journal of Immunology

166

109

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NK cells provide a line of defense against tumors and virus-infected cells that have lost the expression of one or more MHC class I isoforms. Here, we investigate whether inhibitors of apoptosis can block the rejection of tumors mediated by NK cells, by introducing the long form of Fas-associated death domain-like IL-1β-converting enzyme-associated inhibitory protein (FLIPL) and poxvirus cytokine response modifier A (CrmA) into the MHC class I-deficient T lymphoma cell line RMA-S. RMA-S cells do not normally express Fas in vitro, and it was previously postulated that the rejection of these tumors by NK cells is strictly perforin dependent. We show that perforin-deficient NK cells directly mediate Fas up-regulation on RMA-S cells and thereafter kill the cells in a Fas-dependent manner, and that RMA-S FLIPL and RMA-S CrmA are protected from such killing. When injected in immunocompetent recipients, RMA-S cells up-regulate Fas, rendering in vivo-passed mock-transduced cells sensitive to Fas-mediated apoptosis. Moreover, RMA-S FLIPL and RMA-S CrmA cells establish aggressive tumors, in contrast to RMA-S mock cells that are rejected. These results demonstrate that FLIPL and CrmA function as tumor progression factors by protecting MHC class I-deficient tumors from rejection mediated by NK cells. Moreover, our data indicate that death receptor-mediated apoptosis has a more prominent role in the clearance of NK-sensitive tumors than previously suggested.

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“…This assumption is based on recent published studies showing that target cells not expressing Fas do become Fas positive in the presence of Tc cells. This mechanism was identified by using Tc cells from perforin-deficient mice (17).…”

mentioning

confidence: 99%

Creation of Killer Poxvirus Could Have Been Predicted

Müllbacher

Lobigs

2001

J Virol

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Cytotoxic T Cells Specifically Induce Fas on Target Cells, Thereby Facilitating Exocytosis-Independent Induction of Apoptosis

Cited by 37 publications

References 47 publications

Immunization with Murine Breast Cancer Cells Treated with Antisense Oligodeoxynucleotides to Type I Insulin-Like Growth Factor Receptor Induced an Antitumoral Effect Mediated by a CD8+ Response Involving Fas/Fas Ligand Cytotoxic Pathway

Immunization with Murine Breast Cancer Cells Treated with Antisense Oligodeoxynucleotides to Type I Insulin-Like Growth Factor Receptor Induced an Antitumoral Effect Mediated by a CD8+ Response Involving Fas/Fas Ligand Cytotoxic Pathway

A Central Role for Death Receptor-Mediated Apoptosis in the Rejection of Tumors by NK Cells

Creation of Killer Poxvirus Could Have Been Predicted

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