Elena Ambrosino

Publications

• 15.39

  Impact points

  Mouse and human iNKT cell agonist β-mannosylceramide reveals a distinct mechanism of tumor immunity.

  Jessica J O'Konek, Petr Illarionov, Deborah Stewart Khursigara, Elena Ambrosino, Liat Izhak, Bernard F Castillo, Ravinder Raju, Maryam Khalili, Hee-Yong Kim, Amy R Howell, Gurdyal S Besra, Steven A Porcelli, Jay A Berzofsky, Masaki Terabe

  The Journal of clinical investigation. 02/2011; 121(2):683-94.

  Type 1 or invariant NKT (iNKT) cell agonists, epitomized by α-galactosylceramide, protect against cancer largely by IFN-γ-dependent mechanisms. Here we describe what we believe to be a novel IFN-γ-independent mechanism induced by β-mannosylceramide, which also defines a potentially new class of iNKT... [more] Type 1 or invariant NKT (iNKT) cell agonists, epitomized by α-galactosylceramide, protect against cancer largely by IFN-γ-dependent mechanisms. Here we describe what we believe to be a novel IFN-γ-independent mechanism induced by β-mannosylceramide, which also defines a potentially new class of iNKT cell agonist, with an unusual β-linked sugar. Like α-galactosylceramide, β-mannosylceramide directly activates iNKT cells from both mice and humans. In contrast to α-galactosylceramide, protection by β-mannosylceramide was completely dependent on NOS and TNF-α, neither of which was required to achieve protection with α-galactosylceramide. Moreover, at doses too low for either alone to protect, β-mannosylceramide synergized with α-galactosylceramide to protect mice against tumors. These results suggest that treatment with β-mannosylceramide provides a distinct mechanism of tumor protection that may allow efficacy where other agonists have failed. Furthermore, the ability of β-mannosylceramide to synergize with α-galactosylceramide suggests treatment with this class of iNKT agonist may provide protection against tumors in humans.
• 5.65

  Impact points

  Erbb2 DNA vaccine combined with regulatory T cell deletion enhances antibody response and reveals latent low-avidity T cells: potential and limits of its therapeutic efficacy.

  Simona Rolla, Francesco Ria, Sergio Occhipinti, Gabriele Di Sante, Manuela Iezzi, Michela Spadaro, Chiara Nicolò, Elena Ambrosino, Irene Fiore Merighi, Piero Musiani, Guido Forni, Federica Cavallo

  Journal of immunology (Baltimore, Md. : 1950). 06/2010; 184(11):6124-32.

  Rat (r)Erbb2 transgenic BALB-neuT mice genetically predestined to develop multiple invasive carcinomas allow an assessment of the potential of a vaccine against the stages of cancer progression. Because of rErbb2 expression in the thymus and its overexpression in the mammary gland, CD8(+) T cell clo... [more] Rat (r)Erbb2 transgenic BALB-neuT mice genetically predestined to develop multiple invasive carcinomas allow an assessment of the potential of a vaccine against the stages of cancer progression. Because of rErbb2 expression in the thymus and its overexpression in the mammary gland, CD8(+) T cell clones reacting at high avidity with dominant rErbb2 epitopes are deleted in these mice. In BALB-neuT mice with diffuse and invasive in situ lesions and almost palpable carcinomas, a temporary regulatory T cells depletion combined with anti-rErbb2 vaccine markedly enhanced the anti-rErbb2 Ab response and allowed the expansion of latent pools of low-avidity CD8(+) T cells bearing TCRs repertoire reacting with the rErbb2 dominant peptide. This combination of a higher Ab response and activation of a low-avidity cytotoxic response persistently blocked tumor progression at stages in which the vaccine alone was ineffective. However, when diffuse and invasive microscopic cancers become almost palpable, this combination was no longer able to secure a significant extension of mice survival.

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• 6.75

  Impact points

  Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-beta monoclonal antibody.

  Masaki Terabe, Elena Ambrosino, Shun Takaku, Jessica J O'Konek, David Venzon, Scott Lonning, John M McPherson, Jay A Berzofsky

  Clinical cancer research : an official journal of the American Association for Cancer Research. 11/2009; 15(21):6560-9.

  PURPOSE: Transforming growth factor-beta (TGF-beta) is an immunosuppressive cytokine, having direct suppressive activity against conventional CD4(+) and CD8(+)T cells and natural killer cells, thereby inhibiting tumor immunosurveillance. Here, we investigated possible synergy between anti-TGF-beta (... [more] PURPOSE: Transforming growth factor-beta (TGF-beta) is an immunosuppressive cytokine, having direct suppressive activity against conventional CD4(+) and CD8(+)T cells and natural killer cells, thereby inhibiting tumor immunosurveillance. Here, we investigated possible synergy between anti-TGF-beta (1D11) and a peptide vaccine on induction of antitumor immunity, and the mechanisms accounting for synergistic efficacy. EXPERIMENTAL DESIGN: The effect of combination treatment with a peptide vaccine and anti-TGF-beta was examined in a subcutaneous TC1 tumor model, as well as the mechanisms of protection induced by this treatment. RESULTS: Anti-TGF-beta significantly and synergistically improved vaccine efficacy as measured by reduction in primary tumor growth, although anti-TGF-beta alone had no impact. The number of tumor antigen-specific CTL with high functional avidity as measured by IFN-gamma production and lytic activity was significantly increased in vaccinated mice by TGF-beta neutralization. Although TGF-beta is known to play a critical role in CD4(+)Foxp3(+) Treg cells, Treg depletion/suppression by an anti-CD25 monoclonal antibody (PC61) before tumor challenge did not enhance vaccine efficacy, and adding anti-TGF-beta did not affect Treg numbers in lymph nodes or tumors or their function. Also, TGF-beta neutralization had no effect on interleukin-17-producing T cells, which are induced by TGF-beta and interleukin-6. Absence of type II NKT cells, which induce myeloid cells to produce TGF-beta, was not sufficient to eliminate all sources of suppressive TGF-beta. Finally, the synergistic protection induced by anti-TGF-beta vaccine augmentation was mediated by CD8(+) T cells since anti-CD8 treatment completely abrogated the effect. CONCLUSIONS: These results suggest that TGF-beta blockade may be useful for enhancing cancer vaccine efficacy.
• 4.72

  Impact points

  Blockade of TGF-beta enhances tumor vaccine efficacy mediated by CD8(+) T cells.

  Shun Takaku, Masaki Terabe, Elena Ambrosino, Judy Peng, Scott Lonning, John M McPherson, Jay A Berzofsky

  International journal of cancer. Journal international du cancer. 10/2009;

  Though TGF-beta inhibition enhances anti-tumor immunity mediated by CD8(+) T cells in several tumor models, it is not always sufficient for rejection of tumors. In the present study, to maximize the anti-tumor effect of TGF-beta blockade, we tested the effect of anti-TGF-beta combined with an irradi... [more] Though TGF-beta inhibition enhances anti-tumor immunity mediated by CD8(+) T cells in several tumor models, it is not always sufficient for rejection of tumors. In the present study, to maximize the anti-tumor effect of TGF-beta blockade, we tested the effect of anti-TGF-beta combined with an irradiated tumor vaccine in a subcutaneous CT26 colon carcinoma tumor model. The irradiated tumor cell vaccine alone in prophylactic setting significant delayed tumor growth, whereas anti-TGF-beta antibodies alone did not show any anti-tumor effect. However, tumor growth was inhibited significantly more in vaccinated mice treated with anti-TGF-beta antibodies compared to vaccinated mice without anti-TGF-beta suggesting that anti-TGF-beta synergistically enhanced irradiated tumor vaccine efficacy. CD8(+)T cell-depletion completely abrogated the vaccine efficacy, so protection required CD8(+) T cells. Depletion of CD25(+) T regulatory cells led to the almost complete rejection of tumors without the vaccine, whereas anti-TGF-beta?did not change the number of CD25(+) T regulatory cells in un-vaccinated and vaccinated mice. Though the abrogation of CD1d-restricted NKT cells, which have been reported to induce TGF-beta production by MDSC through an IL-13-IL-4R-STAT6 pathway, partially enhanced anti-tumor immunity regardless of vaccination, abrogation of the NKT cell-IL-13-IL-4R-STAT-6 immunoregulatory pathway did not enhance vaccine efficacy. Taken together, these data indicated that anti-TGF-beta enhances efficacy of a prophylactic vaccine in normal individuals despite their not having the elevated TGF-beta levels found in cancer patients and that the effect is not dependent on TGF-beta solely from CD4(+)CD25(+) T regulatory cells or the NKT cell-IL-13-IL-4R-STAT-6 immunoregulatory pathway. (c) 2009 UICC.
• 3.22

  Impact points

  Regulation of tumor immunity: the role of NKT cells.

  Elena Ambrosino, Jay A Berzofsky, Masaki Terabe

  Expert opinion on biological therapy. 07/2008; 8(6):725-34.

  BACKGROUND: Tumor immunosurveillance is a part of the dynamic process of interaction between abnormal cells and the host immune system. Tumor immunosurveillance is actively and continuously regulated in both positive and negative ways. Natural killer T (NKT) cells are cells that have been shown to p... [more] BACKGROUND: Tumor immunosurveillance is a part of the dynamic process of interaction between abnormal cells and the host immune system. Tumor immunosurveillance is actively and continuously regulated in both positive and negative ways. Natural killer T (NKT) cells are cells that have been shown to play a role in both positive and negative regulation of tumor immunosurveillance. Recent studies suggest that NKT cells are a heterogeneous cell population with multiple subsets with distinct functions. OBJECTIVE: This review discusses the functions of those NKT cell subsets in regulating tumor immunity and potential interactions or counter-regulation among the NKT cell subsets. METHOD: Selected literature is reviewed. CONCLUSION: Manipulation of the balance among those subsets may provide new modes of intervention for tumor immunotherapy.

• Mechanisms of suppression of tumor immunosurveillance

  E Ambrosino

  12/2007

  Degree: PhD
• 5.65

  Impact points

  Cross-regulation between type I and type II NKT cells in regulating tumor immunity: a new immunoregulatory axis.

  Elena Ambrosino, Masaki Terabe, Ramesh C Halder, Judy Peng, Shun Takaku, Sachiko Miyake, Takashi Yamamura, Vipin Kumar, Jay A Berzofsky

  Journal of immunology (Baltimore, Md. : 1950). 11/2007; 179(8):5126-36.

  Negative immunoregulation is a major barrier to successful cancer immunotherapy. The NKT cell is known to be one such regulator. In this study we explored the roles of and interaction between the classical type I NKT cell and the poorly understood type II NKT cell in the regulation of tumor immunity... [more] Negative immunoregulation is a major barrier to successful cancer immunotherapy. The NKT cell is known to be one such regulator. In this study we explored the roles of and interaction between the classical type I NKT cell and the poorly understood type II NKT cell in the regulation of tumor immunity. Selective stimulation of type II NKT cells suppressed immunosurveillance, whereas stimulation of type I NKT cells protected against tumor growth even when responses were relatively skewed toward Th2 cytokines. When both were stimulated simultaneously, type II NKT cells appeared to suppress the activation in vitro and protective effect in vivo of type I NKT cells. In the absence of type I, suppression by type II NKT cells increased, suggesting that type I cells reduce the suppressive effect of type II NKT cells. Thus, in tumor immunity type I and type II NKT cells have opposite and counteractive roles and define a new immunoregulatory axis. Alteration of the balance between the protective type I and the suppressive type II NKT cell may be exploited for therapeutic intervention in cancer.
• 7.54

  Impact points

  Immunosurveillance of Erbb2 carcinogenesis in transgenic mice is concealed by a dominant regulatory T-cell self-tolerance.

  Elena Ambrosino, Michela Spadaro, Manuela Iezzi, Claudia Curcio, Guido Forni, Piero Musiani, Wei-Zen Wei, Federica Cavallo

  Cancer research. 09/2006; 66(15):7734-40.

  To assess the role of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells in overcoming immunosurveillance of Erbb2 (HER-2/neu) mammary lesions, we studied the effects of their sustained removal in BALB/c female mice made transgenic for the rat Erbb2 (r-Erbb2) oncogene (BALB-neuT mice), which develop mu... [more] To assess the role of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells in overcoming immunosurveillance of Erbb2 (HER-2/neu) mammary lesions, we studied the effects of their sustained removal in BALB/c female mice made transgenic for the rat Erbb2 (r-Erbb2) oncogene (BALB-neuT mice), which develop multiple mammary carcinomas. During the progression of these lesions, Treg cells expand in the spleen, tumor draining lymph nodes, and tumors. Repeated administration of anti-CD25 antibodies extends tumor-free survival, reduces carcinoma multiplicity, and leads to the manifestation of a natural antibody and CTL-mediated reactivity against r-Erbb2. Loss of Foxp3(+) Treg cells during anti-CD25 treatment remarkably caused the disappearance of Gr1(+) immature myeloid cells, suggesting a cross-talk between these two inhibitory immune cell types. Treg cell expansion associated with r-Erbb2 overexpression may be seen as a physiologic response to dampen the immune reaction elicited by local anomalous overexpression of a self-antigen.
• 5.65

  Impact points

  Timely DNA vaccine combined with systemic IL-12 prevents parotid carcinomas before a dominant-negative p53 makes their growth independent of HER-2/neu expression.

  Tania Pannellini, Michela Spadaro, Emma Di Carlo, Elena Ambrosino, Manuela Iezzi, Augusto Amici, Pier-Luigi Lollini, Guido Forni, Federica Cavallo, Piero Musiani

  Journal of immunology (Baltimore, Md. : 1950). 07/2006; 176(12):7695-703.

  Double transgenic mice overexpressing the transforming rat HER-2/neu oncogene and the mutated p53, with both dominant-negative and a gain-of-function properties, display early aggressive and metastasizing parotid tumors. Multiple acinar and ductal hyperplasia foci overexpressing the HER-2/neu gene p... [more] Double transgenic mice overexpressing the transforming rat HER-2/neu oncogene and the mutated p53, with both dominant-negative and a gain-of-function properties, display early aggressive and metastasizing parotid tumors. Multiple acinar and ductal hyperplasia foci overexpressing the HER-2/neu gene product are evident at wk 5 and progress to poorly differentiated carcinoma by wk 7. Mice die before wk 18 with invasive carcinomas and multiple metastases that no longer express HER-2/neu. A combination of repeated electroporations of plasmids coding for the extracellular and transmembrane domains of the rat HER-2/neu receptor with systemic IL-12 administrations started when the parotids that present diffuse hyperplasia protected all female and 50% of the male mice until the close of the experiment at wk 40. This combined treatment began when multifocal in situ carcinomas that were already present cured 33% of the females and 25% of the males. The most prominent immunologic features associated with the antitumor protection were the production of high titers of anti-HER-2/neu Abs and the nonappearance of cell-mediated cytotoxic reactivity. In conclusion, anti-HER-2/neu vaccination combined with systemic IL-12 control parotid carcinomas as far as p53 mutation makes their growth independent of HER-2/neu expression.
• 9.43

  Impact points

  A DNA vaccine targeting angiomotin inhibits angiogenesis and suppresses tumor growth.

  Lars Holmgren, Elena Ambrosino, Olivier Birot, Carl Tullus, Niina Veitonmäki, Tetyana Levchenko, Lena-Maria Carlson, Piero Musiani, Manuela Iezzi, Claudia Curcio, Guido Forni, Federica Cavallo, Rolf Kiessling

  Proceedings of the National Academy of Sciences of the United States of America. 07/2006; 103(24):9208-13.

  Endogenous angiogenesis inhibitors have shown promise in preclinical trials, but clinical use has been hindered by low half-life in circulation and high production costs. Here, we describe a strategy that targets the angiostatin receptor angiomotin (Amot) by DNA vaccination. The vaccination procedur... [more] Endogenous angiogenesis inhibitors have shown promise in preclinical trials, but clinical use has been hindered by low half-life in circulation and high production costs. Here, we describe a strategy that targets the angiostatin receptor angiomotin (Amot) by DNA vaccination. The vaccination procedure generated antibodies that detected Amot on the endothelial cell surface. Purified Ig bound to the endothelial cell membrane and inhibited endothelial cell migration. In vivo, DNA vaccination blocked angiogenesis in the matrigel plug assay and prevented growth of transplanted tumors for up to 150 days. We further demonstrate that a combination of DNA vaccines encoding Amot and the extracellular and transmembrane domains of the human EGF receptor 2 (Her-2)/neu oncogene inhibited breast cancer progression and impaired tumor vascularization in Her-2/neu transgenic mice. No toxicity or impairment of normal blood vessels could be detected. This work shows that DNA vaccination targeting Amot may be used to mimic the effect of angiostatin.
• 7.54

  Impact points

  p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-neu oncogene-dependent breast tumorigenesis.

  Sara Cabodi, Agata Tinnirello, Paola Di Stefano, Brigitte Bisarò, Elena Ambrosino, Isabella Castellano, Anna Sapino, Riccardo Arisio, Federica Cavallo, Guido Forni, Marina Glukhova, Lorenzo Silengo, Fiorella Altruda, Emilia Turco, Guido Tarone, Paola Defilippi

  Cancer research. 06/2006; 66(9):4672-80.

  To investigate the mechanisms through which p130Cas adaptor protein is linked to tumorigenesis, we generated mouse mammary tumor virus (MMTV)-p130Cas mice overexpressing p130Cas in the mammary gland. MMTVp130Cas transgenic mice are characterized by extensive mammary epithelial hyperplasia during dev... [more] To investigate the mechanisms through which p130Cas adaptor protein is linked to tumorigenesis, we generated mouse mammary tumor virus (MMTV)-p130Cas mice overexpressing p130Cas in the mammary gland. MMTVp130Cas transgenic mice are characterized by extensive mammary epithelial hyperplasia during development and pregnancy and by delayed involution at the end of lactation. These phenotypes are associated with activation of Src kinase, extracellular signal-regulated kinase 1/2, mitogen-activated protein kinase, and Akt pathways, leading to an increased rate of proliferation and a decreased apoptosis. A double-transgenic line derived from crossing MMTV-p130Cas with MMTV-HER2-Neu mice expressing the activated form of the HER2-Neu oncogene develops multifocal mammary tumors with a significantly shorter latency than the HER2-Neu parental strain alone. Mammary epithelial cells isolated from tumors of double-transgenic mice display increased tyrosine phosphorylation, c-Src, and Akt activation compared with cells derived from HER2-Neu tumors. In addition, p130Cas down-regulation by RNA interference increases apoptosis in HER2-Neu-expressing cells, indicating that p130Cas regulates cell survival. Consistently with the double-transgenic mice model, p130Cas is overexpressed in a significant subset of human breast cancers and high levels of p130Cas in association with HER2 expression correlate with elevated proliferation. These findings provide evidences for a role of p130Cas as a positive regulator of both proliferation and survival in normal and transformed mammary epithelial cells. Its overexpression contributes to HER2-Neu-induced breast tumorigenesis, thus identifying this protein as a putative target for clinical therapy.
• 14.51

  Impact points

  A nonclassical non-Valpha14Jalpha18 CD1d-restricted (type II) NKT cell is sufficient for down-regulation of tumor immunosurveillance.

  Masaki Terabe, Jeremy Swann, Elena Ambrosino, Pratima Sinha, Shun Takaku, Yoshihiro Hayakawa, Dale I Godfrey, Suzanne Ostrand-Rosenberg, Mark J Smyth, Jay A Berzofsky

  The Journal of experimental medicine. 01/2006; 202(12):1627-33.

  The importance of immunoregulatory T cells has become increasingly apparent. Both CD4+CD25+ T cells and CD1d-restricted NKT cells have been reported to down-regulate tumor immunity in mouse tumor models. However, the relative roles of both T cell populations have rarely been clearly distinguished in... [more] The importance of immunoregulatory T cells has become increasingly apparent. Both CD4+CD25+ T cells and CD1d-restricted NKT cells have been reported to down-regulate tumor immunity in mouse tumor models. However, the relative roles of both T cell populations have rarely been clearly distinguished in the same tumor models. In addition, CD1d-restricted NKT cells have been reported to play a critical role not only in the down-regulation of tumor immunity but also in the promotion of the immunity. However, the explanation for these apparently opposite roles in different tumor models remains unclear. We show that in four mouse tumor models in which CD1d-restricted NKT cells play a role in suppression of tumor immunity, depletion of CD4+CD25+ T cells did not induce enhancement of immunosurveillance. Surprisingly, among the two subpopulations of CD1d-restricted NKT cells, Valpha14Jalpha18+ (type I) and Valpha14Jalpha18- (type II) NKT cells, type I NKT cells were not necessary for the immune suppression. These unexpected results may now resolve the paradox in the role of CD1d-restricted NKT cells in the regulation of tumor immunity, in that type II NKT cells may be sufficient for negative regulation, whereas protection has been found to be mediated by alpha-galactosylceramide-responsive type I NKT cells.
• 6.75

  Impact points

  Cure of mammary carcinomas in Her-2 transgenic mice through sequential stimulation of innate (neoadjuvant interleukin-12) and adaptive (DNA vaccine electroporation) immunity.

  Michela Spadaro, Elena Ambrosino, Manuela Iezzi, Emma Di Carlo, Pamela Sacchetti, Claudia Curcio, Augusto Amici, Wei-Zen Wei, Piero Musiani, Pier-Luigi Lollini, Federica Cavallo, Guido Forni

  Clinical cancer research : an official journal of the American Association for Cancer Research. 04/2005; 11(5):1941-52.

  PURPOSE: Whereas neoadjuvant therapy is emerging as a treatment option in early primary breast cancer, no data are available on the use of antiangiogenic and immunomodulatory agents in a neoadjuvant setting. In a model of Her-2 spontaneous mammary cancer, we investigated the efficacy of neoadjuvant ... [more] PURPOSE: Whereas neoadjuvant therapy is emerging as a treatment option in early primary breast cancer, no data are available on the use of antiangiogenic and immunomodulatory agents in a neoadjuvant setting. In a model of Her-2 spontaneous mammary cancer, we investigated the efficacy of neoadjuvant interleukin 12 (IL-12) followed by "immune-surgery" of the residual tumor. EXPERIMENTAL DESIGN: Female BALB/c mice transgenic for the rat Her-2 oncogene inexorably develop invasive carcinomas in all their mammary glands by the 23rd week of age. Mice with multifocal in situ carcinomas received four weekly i.p. injections of 100 ng IL-12 followed by a 3-week rest. This course was given four times. A few mice additionally received DNA plasmids encoding portions of the Her-2 receptor electroporated through transcutaneous electric pulses. RESULTS: The protection elicited by IL-12 in combination with two DNA vaccine electroporations kept 63% of mice tumor-free. Complete protection of all 1-year-old mice was achieved when IL-12-treated mice received four vaccine electroporations. Pathologic findings, in vitro tests, and the results from immunization of both IFN-gamma and immunoglobulin gene knockout transgenic mice and of adoptive transfer experiments all show that IL-12 augments the B- and T-cell response elicited by vaccination and slightly decreases the number of regulatory T cells. In addition, IL-12 strongly inhibits tumor angiogenesis. CONCLUSIONS: In Her-2 transgenic mice, IL-12 impairs tumor progression and triggers innate immunity so markedly that DNA vaccination becomes effective at late points in time when it is ineffective on its own.

• Microbes, Tumors and Immune system: Why does Darwin smile?

  A Santoni, E Ambrosino, G Forni

  01/2005;

• DNA vaccination and Interleukin 12 association prevents mammary carcinogenesis in transgenic HER-2/neu mice

  E Ambrosino

  07/2003

  Degree: MSc-PhD