TNF Plays an Essential Role in Tumor Regression after Adoptive Transfer of Perforin/IFN-γ Double Knockout Effector T Cells

Poehlein, Christian; Hu, Hong-Ming; Yamada, Jane; Assmann, Ilka; Alvord, W. Gregory; Urba, Walter J.; Fox, Bernard A.

doi:10.4049/jimmunol.170.4.2004

Cited by 70 publications

(60 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides the two main killing pathways, it has been reported that other killing mechanisms, for example the proinflammatory cytokines gIFN and TNFa, have important roles in rejection of pulmonary metastasis of tumor cells. 38 In the study of Poehlein et al, 31 adoptive transfer of effector T cells, which are taken from perforin and gIFN double knockout mice (PKO/GKO), mediated complete tumor regression and cured wild-type animals with established pulmonary metastasis of melanoma cells by a TNF-a mediated killing mechanism. In addition, Smyth et al 39 have reported that, using the Renca carcinoma tumor model, TRAIL expression on NK and NKT cells has effective antimetastatic functions in vivo mediated by a gIFNdependent immune mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Since perforin, gIFN and TNF-a were identified as critical pathways of effector mechanisms that characterize therapeutic anti-tumor T cells, 31 Hybridoma ascites containing specific antibodies against CD8, gIFN and TNF-a were intravenously injected into C57BL/6 and B6-PKO mice 1 day prior to inoculation of 39.5-B7 cells. Starting on day 6 after tumor cell inoculation, mice were further injected with hybridoma ascites weekly until local tumors were amputated.…”

Section: In Vivo Depletion Of Cd8 T-cells and Neutralization Of Tnf-amentioning

confidence: 99%

See 1 more Smart Citation

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

et al. 2004

View full text Add to dashboard Cite

Perforin/granzyme B-and Fas/FasL-mediated killing pathways are the main effector mechanisms of CTL and NK cells in antitumor immune responses. In this study, we investigated the relative role of these two lytic mechanisms in protection of the host from tumor progression, as well as spontaneous metastasis, using the D122 Lewis lung carcinoma and its gene-modified cells. Utilizing perforin knockout mice (B6-PKO) and Fas and FasL mutant (B6-MRL and B6-Smn) mice, we found that perforin expression in the host plays a crucial function in the prevention of metastasis. However, local tumor rejection of an H-2K b and B7-1 transfectant, 39.5-B7 cells, was not dependent either on perforin or Fas/FasL expression in vivo. In addition, CTL lysis of 39.5-B7 cells was independent of perforin and Fas/FasL interactions in 18-hour in vitro assays. We also confirmed that CD8 T-cells were responsible for rejecting 39.5-B7 local tumors, yet cytokines, TNF-a and gIFN were not involved in tumor rejection in vivo. Furthermore, blocking assays using caspase inhibitors (zVAD-fmk, zIETD-fmk and zLEHD-fmk) showed that, whereas caspase activation was partially required to induce 39.5-B7 lysis mediated by the perforin-dependent pathway, 39.5-B7 lysis by CTLs through the perforin-independent mechanism required caspase activation. Thus, these results suggested that perforin, Fas/FasL, gIFN and TNF-a independent lytic mechanisms, mediated by CD8 T cells, have a crucial role in rejection of 39.5-B7 cells in vivo. Caspase activation is a pre requisite for apoptosis of targets by CTLs

show abstract

Section: Discussionmentioning

confidence: 99%

Section: In Vivo Depletion Of Cd8 T-cells and Neutralization Of Tnf-amentioning

confidence: 99%

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

et al. 2004

View full text Add to dashboard Cite

show abstract

“…It has been reported that the mechanism of in vivo CD8 þ T-cell-mediated tumor regression is distinct from that of in vitro CD8 þ T-cell-mediated cytotoxicity, and is independent of perforin and FasL by using CD8 þ T cells with perforin gene knockout or FasL mutant 51,52 Recently, Hollenbaugh et al 53 demonstrated that CD8 þ T cell-secreted, but not the host-derived IFN-g play an important role in eradication of solid tumors by regulating CD8 þ T-cell expansion and migration and inducing tumor cell apoptosis. Blohm et al 54 visualized adoptive CD8 þ T-cell-mediated tumor destruction and found that tumors 'melt' from the inside were derived from destruction of tumor vasculature and accumulation of granulocytes.…”

Section: Discussionmentioning

confidence: 99%

“…The enhancement of in vivo therapeutic effect of the engineered T TNF cells observed in this study may not be due to its upregulated expression of perforin, but may be associated with its enhanced secretion of the transgenecoded human TNF-a as well as its elongated survival in vivo. TNF-a plays an essential role in CD8 þ T-cellmediated elimination of tumors in vivo 52,55 possibly by its direct cytotoxicity to tumor cells leading apoptosis through engagement of the p55 TNF-a receptor I. 56 The inflammatory cytokine TNF-a also activates macrophages, natural killer cells and T cells 20,57 by its binding to the p75 TNF-a receptor II (TNFRII).…”

Section: Discussionmentioning

confidence: 99%

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

Shi

Chan

et al. 2007

Cancer Gene Ther

View full text Add to dashboard Cite

T-cell suppression derived from tumor-secreted immunosuppressive interleukin (IL)-10 becomes a major barrier to CD8 þ T-cell immunotherapy of tumors. Tumor necrosis factor-alpha (TNF-a) is a multifunctional cytokine capable of activating T and dendritic cells (DCs) and counteracting IL-10-mediated DC inhibition and regulatory T-cell-mediated immune suppression. In this study, we constructed a recombinant adenovirus MF AdVTNF with fiber-gene modified by RGD insertion into the viral knob's H1 loop and a melanoma cell line B16 OVA/ILÀ10 engineered to express ovalbumin (OVA) and to secrete IL-10 (2.2 ng/ml/10 6 cells/24 h). We transfected OVA-specific CD8 þ T cells with MF AdVTNF, and found a fivefold increase in transgene human TNF-a secretion (4.3 ng/ ml/10 6 cells/24 h) by the engineered CD8 þ T TNF cells transfected with MF AdVTNF, compared to that (0.8 ng/ml/10 6 cells/24 h) by CD8 þ T cells transfected with the original AdVTNF without viral fiber modification. The engineered CD8 þ T TNF cells exhibited enhanced cytotoxicity and elongated survival in vivo after adoptive transfer. TNF-a derived from both the donor CD8 þ T cells and the host cells plays an important role in donor CD8 þ T-cell survival in vivo after adoptive transfer. We also demonstrated that the transfected B16 OVA/ILÀ10 tumor cells secreting IL-10 are more resistant to in vivo CD8 þ T-cell therapy than the original B16 OVA tumor cells without IL-10 expression. Interestingly, the engineered CD8 þ T TNF cells secreting transgene-coded TNF-a, but not the control CD8 þ T control cells without any transgene expression eradicated IL-10-secreting 12-day lung micrometastasis in all 10/10 mice and IL-10-secreting solid tumors (B5 mm in diameter) in 6/10 mice. Transfer of the engineered CD8 þ T TNF cells further induced both donor-and host-derived memory CD8 þ T cells, leading to a stronger long-term antitumor immunity against the IL-10-secreting B16 OVA/ILÀ10 tumor cell challenges. Therefore, CD8 þ T cells engineered to secrete TNF-a may be useful when designing strategies for adoptive T-cell therapy of solid tumors.

show abstract

“…An early study in mice revealed that rejection of pulmonary metastases by cultured tumorspecific CD8 T cells correlates better with their capacity to produce IFN-c than with their cytotoxicity in vitro [18]. More recent studies using IFN-c-deficient mice have provided compelling evidence for the important role of IFN-c in T cell-mediated tumor cell rejection [7,9,10,13,14,[19][20][21][22][23][24][25][26]. Various possibilities can be envisaged to explain the anti-tumor activity of IFN-c: first, IFN-c is known to increase MHC expression and antigen presentation, thereby rendering tumor target cells more susceptible to CTL attack [27][28][29].…”

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

View full text Add to dashboard Cite

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.

show abstract

TNF Plays an Essential Role in Tumor Regression after Adoptive Transfer of Perforin/IFN-γ Double Knockout Effector T Cells

Cited by 70 publications

References 46 publications

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

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

Contact Info

Product

Resources

About