Effector Cell-Derived Lymphotoxin α and Fas Ligand, but not Perforin, Promote Tc1 and Tc2 Effector Cell-Mediated Tumor Therapy in Established Pulmonary Metastases

Dobrzanski, Mark J.; Reome, Joyce B.; Hollenbaugh, Joseph A.; Hylind, James C.; Dutton, Richard

doi:10.1158/0008-5472.can-03-2580

Cited by 33 publications

(24 citation statements)

References 63 publications

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“…Although we showed that such Fas low -TEV were responsive to the perforin pathway in this model, it is conceivable that in circumstances whereby the Fas/FasL pathway may actually be the dominant mechanism of T cell-mediated tumor rejection (44,45) or the perforin pathway may not be triggered efficiently (46), such a Fasbased escape mechanism may have broader adverse implications for the immunotherapy outcome.…”

Section: Discussionmentioning

confidence: 62%

CTL Adoptive Immunotherapy Concurrently Mediates Tumor Regression and Tumor Escape

Liu

Caldwell

Greeneltch

et al. 2006

The Journal of Immunology

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Tumor escape and recurrence are major impediments for successful immunotherapy. It is well-documented that the emergence of Ag-loss variants, as well as regulatory mechanisms suppressing T cell function, have been linked to inadequate antitumor activity. However, little is known regarding the role of Fas-mediated cytotoxicity by tumor-specific CD8+ CTL in causing immune evasion of Fas resistant variants during adoptive immunotherapy. In this study, we made use of an adoptive transfer model of experimental lung metastasis using tumor-specific CTL as a relevant immune-based selective pressure, and wherein the Fas ligand pathway was involved in the antitumor response. Surviving tumor cells were recovered and examined for alterations in antigenic, functional, and biologic properties. We showed that diminished susceptibility to Fas-mediated cytotoxicity in vivo was an important determinant of tumor escape following CTL-based immunotherapy. Tumor escape variants (TEV) recovered from the lungs of CTL-treated mice exhibited more aggressive behavior in vivo. However, these TEV retained relevant MHC class I and tumor Ag expression and sensitivity to CTL via the perforin pathway but reduced susceptibility to Fas-mediated lysis. Moreover, TEV were significantly less responsive to eradication by CTL adoptive immunotherapy paradigms as a consequence of increased Fas resistance. Overall, we identified that Faslow-TEV emerged as a direct consequence of CTL-tumor interactions in vivo, and that such an altered neoplastic Fas phenotype compromised immunotherapy efficacy. Together, these findings may have important implications for both tumor progression and the design of immunotherapeutic interventions to confront these selective pressures or escape mechanisms.

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Section: Discussionmentioning

confidence: 62%

CTL Adoptive Immunotherapy Concurrently Mediates Tumor Regression and Tumor Escape

Liu

Caldwell

Greeneltch

et al. 2006

The Journal of Immunology

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“…We had previously shown that in vitro cytolytic activity of Tc1 effectors from OT-1 mice was Ͼ99% perforin dependent in the standard 4-h chromium release assay (16,17) and was undiminished in Tc1 or Tc2 effectors from either Fas-L or TNF-␣/LT-␣-deficient mice. We realized that we were comparing a 4-h in vitro assay with an in vivo killing that might take place over a period of days rather than hours.…”

Section: Discussionmentioning

confidence: 99%

The Rate of the CD8-Dependent Initial Reduction in Tumor Volume Is Not Limited by Contact-Dependent Perforin, Fas Ligand, or TNF-Mediated Cytolysis

Hollenbaugh

Reome

Dobrzanski

et al. 2004

The Journal of Immunology

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Established EG7 tumors expressing OVA and growing at an intradermal site become rapidly reduced in size following adoptive therapy with in vitro-generated type I CD8 T cell (Tc1) effectors generated from naive CD8 T cells from transgenic TCR OVA-specific mice. Tc1 effectors kill EG7 target cells in vitro by a perforin-dependent mechanism. However, we show that there is no quantitative diminution of the initial phase of antitumor activity in vivo, whether the Tc1 effectors are derived from perforin-, Fas ligand-, or TNF-deficient transgenic TCR mice or whether the recipients are perforin deficient. Tumors are also equally well controlled whether the Tc1 effectors come from mice deficient in perforin plus Fas ligand or perforin plus TNF. Control of tumor growth is diminished when Tc1 effectors generated from IFN-γ-deficient mice are used. We conclude that control of tumor growth is not in any way affected by loss of contact-mediated lytic mechanisms, and conclude that the CD8 effectors must act by recruiting host effector mechanisms to control tumor growth.

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“…Perforin-deficient mice were reported to be more susceptible to tumor development in some models [5][6][7][8], while other studies found that perforin-deficient CTL were fully capable of exerting anti-tumor activity in vivo [9][10][11][12][13]. Similarly, CD95L-dependent effector mechanisms have been shown to be important in some models [14][15][16] but not in others [9,13,17]. The release of soluble factors represents an additional mechanism by which CD8 T cells could exert anti-tumor activity.…”

Section: Introductionmentioning

confidence: 99%

Solid tumors “melt” from the inside after successful CD8 T cell attack

Blohm¹,

Potthoff²,

Kogel³

et al. 2006

Eur J Immunol

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Adoptive transfer of tumor-specific T cells represents a promising approach for cancer immunotherapy. Here, we visualized the anti-tumor response of CD8 T cells from P14 TCR-transgenic mice specific for the model antigen GP33 by immunohistology. P14 T cells, adoptively transferred into tumor-bearing hosts, induced regression of established 3LL-A9 GP33 and MCA102 GP33 tumors that express GP33 as a tumor-associated model antigen. Strikingly, the visible effects of P14 T cell attack, such as the destruction of the tumor vasculature and accumulation of granulocytes, were predominantly detected inside the tumor mass. In regressing tumors, P14 T cells were found in the intact rim zone but not in central areas that were infiltrated with granulocytes and lacked CD31 + endothelial cells. The rim of P14 T cell-treated tumors showed an increase in vascular density and decrease in hypoxia compared to untreated tumors. Hypoxic areas of tumors are known to exhibit decreased sensitivity to radiation therapy or chemotherapy. Thus, our data also imply that adoptive transfer of tumor-specific CD8 T cells might synergize with radiation therapy or chemotherapy in the elimination of solid tumors in vivo.

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Effector Cell-Derived Lymphotoxin α and Fas Ligand, but not Perforin, Promote Tc1 and Tc2 Effector Cell-Mediated Tumor Therapy in Established Pulmonary Metastases

Abstract: ABSTRACT

Cited by 33 publications

References 63 publications

CTL Adoptive Immunotherapy Concurrently Mediates Tumor Regression and Tumor Escape

CTL Adoptive Immunotherapy Concurrently Mediates Tumor Regression and Tumor Escape

The Rate of the CD8-Dependent Initial Reduction in Tumor Volume Is Not Limited by Contact-Dependent Perforin, Fas Ligand, or TNF-Mediated Cytolysis

Solid tumors “melt” from the inside after successful CD8 T cell attack

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