Differential requirement of perforin and IFN-γ in CD8 T cell-mediated immune responses against B16.F10 melanoma cells expressing a viral antigen

Prévost-Blondel, Armelle; Neuenhahn, Michael; Rawiel, Marlies; Pircher, Hanspeter

doi:10.1002/1521-4141(200009)30:9<2507::aid-immu2507>3.0.co;2-v

Cited by 47 publications

(27 citation statements)

References 24 publications

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“…This suggests that rapid tumor cell lysis by P14 IL-2 cells was of minor importance for tumor cell control in our model system. Elimination of B16 gp33 pulmonary metastases by activated P14 T cells requires IFN-g but does not depend on perforin-mediated cell lysis [17]. P14 IL-2 cells were efficient in IFN-g production but nevertheless failed to lower pulmonary metastases.…”

Section: Discussionmentioning

confidence: 93%

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

2008

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We determined the efficacy of in vitro expanded P14 TCR transgenic CD8 T cells to mediate tumor cell elimination and to protect against viral infection in mice. Contrary to previous studies, an adoptive transfer model without lymphodepletion, vaccination or cytokine treatment was used. Antigen-activated P14 T cells cultured in IL-2-containing medium for 7 days (P14 IL-2 ) exhibited potent effector cell functions in vitro but did not confer protection against melanoma growth or viral infection. In contrast, P14 T cells cultured in IL-15 (P14 ) were highly effective in vivo although they displayed only moderate effector functions in vitro. Therapeutic efficacy correlated with the survival of the transferred T cells in the recipients: P14 IL-2 cells disappeared rapidly whereas P14 IL-15 cells persisted for prolonged time. Decreasing the IL-2 concentration in the culture media improved in vivo survival and efficacy but also lowered the cell yield of the cultures. Finally, we could extend the findings with monoclonal P14 T cells to polyclonal CD8 T cells. Thus, in vitro expansion of antigen-specific CD8 T cells in IL-15 allowed the generation of substantial numbers of T cells without inducing terminally differentiated effector cells that turned out to be unfavorable in the transfer model examined here.Key words: Cytotoxic T cells . Rodent . Tumor immunity . Viral IntroductionAdoptive transfer of antigen-specific CD8 T cells into hosts represents a promising approach to treat tumors and viral infections [1][2][3][4]. To generate sufficient numbers of T cells for this therapy, T cells have to be stimulated and expanded in vitro. In most protocols used today, IL-2 is added to the culture medium to ensure T-cell proliferation, differentiation and survival. Besides IL-2, IL-15 also supports CD8 T-cell growth [5]; however, the phenotype and the functional activity of IL-2-versus IL-15-cultured CD8 T cells differ considerably. Manjunath et al. [6] were the first to show that CD8 T cells from P14 TCR-tg mice specific for gp33 epitope of lymphocytic choriomeningitis virus (LCMV) acquired an effector memory phenotype with high cytolytic activity when cultured in the presence of IL-2 whereas addition of IL-15 led to a central memory phenotype with low effector cell functions. Further analysis in the same TCR transgenic system revealed that these two cytokines were equivalent mitogens for antigen-stimulated CD8 T cells but that IL-2 was more potent in inducing amino acid uptake and protein synthesis [7].For adoptive T-cell therapy, it is important to generate CD8 T cells in vitro, which are efficient in inducing tumor regression or virus clearance in vivo. The degree of specific target cell lysis and the amount of antigen-triggered IFN-g production are frequently used to predict the efficacy of CD8 T cells in vivo. However, several recent studies in the pmel-1 TCR-tg model specific for the self/tumor antigen gp100 of B16 melanoma cells indicated that antigen-stimulated CD8 T cells with a less differentiated phenotype were sup...

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Section: Discussionmentioning

confidence: 93%

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

2008

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“…To assess such a hypothesis, we monitored the tumor-specific IFN-␥ response in MT/ret melanoma mice and compared it with the response in mice with concurrent vitiligo. Many reports have indicated that IFN-␥ plays a critical role in the development of tumor immunity, and recent reports including ours using IFN-␥ knock-out mice demonstrated a crucial role for IFN-␥ in the control of B16 melanoma growth in vivo (15)(16)(17). To evaluate natural tumor-specific response, ex vivo IFN-␥-ELISPOT assays were performed by using PBLs isolated from MT/ret mice as effector cells and a Melan-ret cell line as melanoma antigen-presenting cells.…”

Section: Treatment With Heavy Metal Leads To Vitiligo Development In mentioning

confidence: 92%

Spontaneous Vitiligo in an Animal Model for Human Melanoma

Lengagne

Gal²,

Garcette

et al. 2004

Cancer Research

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Tumor antigen-reactive T cells can be detected in a large proportion of melanoma patients, but their efficacy on tumor control in vivo remains unclear. On the other hand, vitiligo, a skin disorder characterized by patchy depigmented macules, may occur spontaneously or after antitumor therapies. Moreover, vitiligo is significantly associated with positive clinical response, but the mechanism is not understood. Therefore, the establishment of a relevant animal model in which melanoma and vitiligo spontaneously develop stepwise may be useful for better understanding of the parameters involved in the destruction of both benign and malignant melanocytes. In a previous work, we established a mouse model for melanoma in which MT/ret transgenic mice express the ret oncogene fused to the metallothionein promoter. Here we report that melanoma leads to spontaneous vitiligo. We further investigate, for the first time in this model, the natural antitumor T-cell response and evaluate the role of cellular immunity in the development of the disease. Interestingly, the occurrence of spontaneous tumor nodules in MT/ret mice with melanomaassociated vitiligo is significantly delayed when compared in melanoma mice without vitiligo. Moreover, a significant proportion of mice with melanoma-associated vitiligo resisted a challenge with syngeneic melanoma cells in contrast to animals without vitiligo. Our results confirm that vitiligo is associated with clinical benefit and further demonstrate the crucial role of CD8 ؉ T cells for tumor control in melanoma-associated vitiligo.

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“…The importance of these effector molecules in T cell-mediated tumor cell rejection has been examined by numerous studies using gene-deficient mice. 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].…”

Section: Introductionmentioning

confidence: 99%

“…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

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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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Differential requirement of perforin and IFN-γ in CD8 T cell-mediated immune responses against B16.F10 melanoma cells expressing a viral antigen

Cited by 47 publications

References 24 publications

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

Spontaneous Vitiligo in an Animal Model for Human Melanoma

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

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