IFN-γ and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy

Wigginton, Jon M.; Gruys, Eilene; Geiselhart, Lisa; Subleski, Jeffrey; Komschlies, Kristin L.; Park, Jong‐Wook; Wiltrout, Theresa A.; Nagashima, Kunio; Back, Timothy C.; Wiltrout, Robert H.

doi:10.1172/jci200110128

Cited by 110 publications

(52 citation statements)

References 43 publications

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“…However, in contrast to the tumors used in these studies, the Renca tumor we used is very sensitive to FasLmediated lysis. We were unable to generate anti-Renca CTL from BALB/c gld/gld or IFN-␥ Ϫ/Ϫ mice using our protocol, because these mice do not respond to in vivo immunotherapy (4). Interestingly, the transfer of WT BALB/c anti-Renca CTL plus neutralizing Ab to FasL did not block the antitumor effects in the pulmonary metastasis model (data not shown), suggesting FasL may not be crucial for the destruction of Renca lung metastases.…”

Section: Discussionmentioning

confidence: 98%

“…S ome human renal cell carcinomas (RCC) 4 as well as the Renca mouse RCC respond to cytokine-based immunotherapies. In particular, regimens containing IL-2 have shown efficacy in both man and mouse (1).…”

mentioning

confidence: 99%

“…For these studies, CD8 ϩ T cells have been consistently implicated as critical components for tumor regression in vivo. However, the nature of the requisite effector functions of T cells critical for therapeutic benefits in vivo have not been identified, although the generation of IFN-␥ was also found to be essential for the success of immunotherapy (4).…”

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confidence: 99%

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Tumor-Specific CTL Kill Murine Renal Cancer Cells Using Both Perforin and Fas Ligand-Mediated Lysis In Vitro, But Cause Tumor Regression In Vivo in the Absence of Perforin

Seki

Brooks

Carter

et al. 2002

The Journal of Immunology

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119

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Kidney cancer is a devastating disease; however, biological therapies have achieved some limited success. The murine renal cancer Renca has been used as a model for developing new preclinical approaches to the treatment of renal cell carcinoma. Successful cytokine-based approaches require CD8+ T cells, but the exact mechanisms by which T cells mediate therapeutic benefit have not been completely identified. After successful biological therapy of Renca in BALB/c mice, we generated CTLs in vitro using mixed lymphocyte tumor cultures. These CTL mediated tumor-specific H-2Kd-restricted lysis and production of IFN-γ, TNF-α, and Fas ligand (FasL) in response to Renca. CTL used both granule- and FasL-mediated mechanisms to lyse Renca, although granule-mediated killing was the predominant lytic mechanism in vitro. The cytokines IFN-γ and TNF-α increased the sensitivity of Renca cells to CTL lysis by both granule- and FasL-mediated death pathways. Adoptive transfer of these anti-Renca CTL into tumor-bearing mice cured most mice of established experimental pulmonary metastases, and successfully treated mice were immune to tumor rechallenge. Interestingly, we were able to establish Renca-specific CTL from mice gene targeted for perforin (pfp−/−) mice. Although these pfp−/− CTL showed reduced cytotoxic activity against Renca, their IFN-γ production in the presence of Renca targets was equivalent to that of wild-type CTL, and adoptive transfer of pfp−/− CTL was as efficient as wild-type CTL in causing regression of established Renca pulmonary metastases. Therefore, although granule-mediated killing is of paramount importance for CTL-mediated lysis in vitro, some major in vivo effector mechanisms clearly are independent of perforin.

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Section: Discussionmentioning

confidence: 98%

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confidence: 99%

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Tumor-Specific CTL Kill Murine Renal Cancer Cells Using Both Perforin and Fas Ligand-Mediated Lysis In Vitro, But Cause Tumor Regression In Vivo in the Absence of Perforin

Seki

Brooks

Carter

et al. 2002

The Journal of Immunology

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119

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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%

“…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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