CD4 T cells inhibit <i>in vivo</i> the CD8‐mediated immune response against murine colon carcinoma cells transduced with interleukin‐12 genes

Martinotti, Alessia; Stoppacciaro, Antonella; Vagliani, Maddalena; Melani, Cecilia; Spreafico, Fabio; Wysocka, Maria; Parmiani, Giorgio; Trinchieri, Giorgio; Colombo, Mario P.

doi:10.1002/eji.1830250124

Cited by 114 publications

(68 citation statements)

References 36 publications

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“…The elimination of CD4 + cells from mice bearing CT-26 colon adenocarcinoma dramatically potentiates antitumor activity of IL-12, and depletion of CD4 + cells has significantly increased the survival of Renca -and CT26 -bearing mice. 12,21 Taken together, these findings indicate that the decreased CD4 + cells we observed in our study may also contribute to the antitumor activity in our model.…”

Section: Discussionsupporting

confidence: 76%

Intramuscular electroporation delivery of IL-12 gene for treatment of squamous cell carcinoma located at distant site

et al. 2001

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Gene therapy with IL -12 has been shown to elicit potent systemic antitumor response in a variety of tumors. Although direct intratumoral injection is the most commonly used delivery route for gene therapy of solid tumors, the skeletal muscle has been shown to be an ideal tissue for gene delivery to produce systemic gene expression. We have previously demonstrated that electroporation delivery of a reporter gene to muscle enhances the transfection efficiency and the level of gene expression by two to three logs. We report here that intramuscular ( i.m. ) injection of as little as 10 g of the IL -12 DNA plasmid followed by electroporation prevents squamous cell carcinoma ( SCCVII ) tumor establishment in up to 40% of experimental animals and reduces the volume of established tumors by 75% compared to controls ( P < .05 ) . By comparison, there was no difference in tumor growth observed between IL -12 injection alone and injection of empty vector with or without electroporation. The induction of antitumor activity by i.m. electroporation delivery of the IL -12 gene is associated with an increase in IL -12 expression in muscle and serum. The level of IL -12 expression in muscle and serum was 1500 pg / tibialias muscle and 170 pg / mL serum, respectively, at day 6, after the gene was delivered by electroporation. In contrast, the level of IL -12 when the gene was injected without electroporation was hardly detectable after subtracting the background level of IL -12 detected in naõ Ève mice. The high level of IL -12 expression led to a 170 -fold induction of IFN -expression in serum at day 6 after i.m. electroporation delivery of IL -12 DNA plasmid, which was equal to 1450 pg / mL in the serum. The induction of antitumor activity by i.m. electroporation delivery of the IL -12 gene also correlates with increased CD8 + T -cell population in peripheral blood but not in spleen. Our findings suggest that i.m. delivery of IL -12 gene using electroporation is an effective method of inducing a systemic antitumor response against SCC. Cancer Gene Therapy ( 2001 ) 8, 151 ± 157

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Section: Discussionsupporting

confidence: 76%

Intramuscular electroporation delivery of IL-12 gene for treatment of squamous cell carcinoma located at distant site

et al. 2001

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“…The overexpression of IL-12 in B16 melanoma, thricostatin-A (TSA) mammary adenocarcinoma and C26 colon carcinoma cells induced tumor suppression upon subcutaneous (s.c.) inoculation. [43][44][45][46] Whereas in B16 melanoma this effect was mediated by a subset of innate lymphoid cells (ILCs), the By using mice lacking IL-23, IL-23 receptor or anti-IL23p19 blocking antibodies, endogenous IL-23 was shown to promote tumor growth in different tumor models. 142,143 In colorectal carcinoma, the effects of IL-23 were mimicked after blocking IL-17A.…”

Section: Mechanisms Of Tumor Protection Through Il-12mentioning

confidence: 99%

New insights into IL-12-mediated tumor suppression

et al. 2014

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During the past two decades, interleukin-12 (IL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models. Through pleiotropic effects on different immune cells that form the tumor microenvironment, IL-12 establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines depending on the type of tumor or the affected tissue. The robust antitumor response exerted by IL-12, however, has not yet been successfully translated into the clinics. The majority of clinical trials involving treatment with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects. Here we discuss the therapeutic effects of IL-12 from preclinical to clinical studies, and will highlight promising strategies to take advantage of the antitumor activity of IL-12 while limiting adverse effects.

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“…Martinotti et al have shown that the systemic effect of rIL-12 was linked to the time of treatment, because B16 tumors partially regressed in response to IL-12 but resumed growth after interruption of cytokine treatment. 48 As observed in the B16F1 model, there was no difference between the combination of IL-2 and IL-12 and IL-2 (T:F ratio ϭ 1:5:5) alone in mice bearing B16F0 melanoma. B16F0 tumor establishment was delayed in those mice receiving IL-2-transduced fibroblasts (T:F ratio ϭ 1:10) or a mixture of IL-2-and IL-12-transduced fibroblasts compared with tumor cells alone with or without untransduced fibroblasts.…”

Section: Discussionmentioning

confidence: 69%

Retroviral-mediated transfer of genes encoding interleukin-2 and interleukin-12 into fibroblasts increases host antitumor responsiveness

et al. 1999

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The transfer of genes encoding cytokines into tumor cells has emerged as a new strategy to increase in vivo host reactivity to a variety of tumors. Because gene transfer into tumor cells cannot be easily applied in the clinical setting, we have developed an experimental model of gene transfer into fibroblasts and examined the capacity of these engineered cells to elicit an antitumor immune response. Interleukin-12 (IL-12) is a heterodimeric cytokine with pleiotropic activities presenting strong antitumor and antimetastatic effects in murine models. A bicistronic retroviral vector was constructed that contained the cDNAs encoding both chains (p40 and p35) of murine IL-12 separated by an internal ribosomal entry site sequence. Syngeneic cutaneous fibroblasts obtained from newborn mice and transduced to secrete either IL-12 or IL-2 were injected subcutaneously with B16F0 or B16F1 melanoma cells. The time of tumor occurrence and overall survival of mice were significantly prolonged when B16F1 cells were coinjected with cytokine-producing fibroblasts compared with B16F1 alone or B16F1 together with unmanipulated fibroblasts. Systemic effects were seen in the mice injected with either IL-2-or IL-12-secreting fibroblasts, with the highest proliferation capability and interferon-␥ production observed in vitro from splenocytes from recipients of IL-2-secreting fibroblasts. Injection of IL-2-secreting fibroblasts or coinjection of IL-2-and IL-12-producing fibroblasts resulted in a significant increase of survival in the B16F0 model; in some cases, complete disease eradication was observed. These results suggest that cutaneous fibroblasts represent a target of choice for gene transfer and would be useful in the treatment of minimal residual disease in humans.

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CD4 T cells inhibit in vivo the CD8‐mediated immune response against murine colon carcinoma cells transduced with interleukin‐12 genes

Cited by 114 publications

References 36 publications

Intramuscular electroporation delivery of IL-12 gene for treatment of squamous cell carcinoma located at distant site

Intramuscular electroporation delivery of IL-12 gene for treatment of squamous cell carcinoma located at distant site

New insights into IL-12-mediated tumor suppression

Retroviral-mediated transfer of genes encoding interleukin-2 and interleukin-12 into fibroblasts increases host antitumor responsiveness

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