PubMed | Molecular Targeting Unit, Fondazione IRCCS Instituto Nazionale dei Tumori and University of Milan
Type: Journal Article | Journal: Oncoimmunology | Year: 2016
Due to their constant exposure to inhaled antigens, lungs represent a particularly immunosuppressive environment that limits excessive immune responses; however, cancer cells can exploit this unique environment for their growth. We previously described the ability of aerosolized CpG-ODN combined with Poly(I:C) (TLR9 and TLR3 agonists, respectively) to promote antitumor immunity in a B16 melanoma lung metastasis model. Here, we explored the possibility of improving the therapeutic efficacy of TLR9/TLR3 agonist combinations by including in the inhalant either an antibody directed to both Ly6G and Ly6C markers to locally deplete myeloid-derived suppressive cells (MDSCs) or IFN to directly activate the natural killer (NK) and macrophage innate immune cells in the lung. Addition of nebulized anti-MDSC antibody RB6-8C5 to aerosolized CpG-ODN/Poly(I:C) resulted in reduced mRNA levels of immunsuppressive molecules (IL10, Arg-1, and Nos2), increased activation of resident NK cells and improved treatment outcome, with a significant reduction in established B16 melanoma lung metastases compared to treatment with CpG-ODN/Poly(I:C) alone. Likewise, addition of aerosolized IFN led to increased mRNA levels of proinflammatory cytokines (IL15 and IFN) in the lung and recruitment of highly activated NK cells, with no evident signs of toxicity and with a significantly improved antitumor effect as compared with aerosolized CpG-ODN/Poly(I:C). Combining both IFN and RB6-8C5 with CpG-ODN/Poly(I:C) did not produce an additive effect compared to IFN + CpG-ODN/Poly(I:C) or RB6-8C5 + CpG-ODN/Poly(I:C). Our results indicate that the inhalation therapy is a feasible and non-invasive strategy to deliver immunodulatory molecules, including antibodies and cytokines that reprogram the lung tumor microenvironment to foster immune destruction of tumors.
Giussani M.,University of Milan |
Cardone M.F.,University of Bari |
Cardone M.F.,Molecular Targeting Unit |
Bodega B.,University of Milan |
And 4 more authors.
Genomics | Year: 2012
We performed a detailed genomic investigation of the chimpanzee locus syntenic to human chromosome 4q35.2, associated to the facioscapulohumeral dystrophy. Two contigs of approximately 150. kb and 200. kb were derived from PTR chromosomes 4q35 and 3p12, respectively: both regions showed a very similar sequence organization, including D4Z4 and Beta satellite linked clusters. Starting from these findings, we derived a hypothetical evolutionary history of human 4q35, 10q26 and 3p12 chromosome regions focusing on the D4Z4-Beta satellite linked organization. The D4Z4 unit showed an open reading frame (DUX4) at both PTR 4q35 and 3p12 regions; furthermore some subregions of the Beta satellite unit showed a high degree of conservation between chimpanzee and humans. In conclusion, this paper provides evidence that at the 4q subtelomere the linkage between D4Z4 and Beta satellite arrays is a feature that appeared late during evolution and is conserved between chimpanzee and humans. © 2012 Elsevier Inc.
Tagliabue E.,Molecular Targeting Unit |
Balsari A.,University of Milan |
Campiglio M.,Molecular Targeting Unit |
Pupa S.M.,Molecular Targeting Unit
Expert Opinion on Biological Therapy | Year: 2010
Importance of the field: Differential levels of HER2 expression in normal versus HER2-overexpressing breast carcinomas, together with the demonstration of a key role for HER2 in tumor progression, make HER2 an ideal target for specific therapeutic approaches. Areas covered in this review: This review considers the clinical value of trastuzumab and lapatinib, the two HER2-targeted therapies approved for clinical practice. References were chosen by searching the PubMed and MEDLINE datasets using as search term: 'HER2', in association with 'prognosis', 'response', 'trastuzumab', 'lapatinib' and 'resistance'. What the reader will gain: This review deals with HER2 as a target for breast carcinoma treatment, focusing on anti-HER2 therapies used in clinical practice, their merits and shortcomings. Take home message: The benefit of anti-HER2 therapies demonstrated in clinical trials indicates that HER2 is, to date, one of the most promising molecules for targeted therapy. Nevertheless, since tumor cells utilizing alternative growth signaling pathways through transmembrane receptors as well as intracellular signaling transduction molecules can bypass HER2 blockade, a future ambitious aim is the successful combination of anti-HER2 strategies with drugs directed to molecules that contribute to anti-HER2 resistance. © 2010 Informa UK Ltd.
PubMed | Molecular Targeting Unit
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2014
Currently used CA15-3 and CEA have found their clinical application particularly in the follow-up of patients with advanced disease. Novel biomarkers are urgent, especially for improving early diagnosis as well as for discriminating between benign and malignant disease.In the present study, we used a proteomic approach based on surface-enhanced laser desorption/ionization-time of flight-mass spectrometry screening with the aim of identifying differentially expressed 2-30 kDa proteins in plasma of patients with malignant (65 cases) and benign (88 cases) breast lesions with respect to 121 healthy controls.We found that the most promising SELDI peaks were those corresponding to hepcidin-25 and ferritin light chain. We evaluated the capability of these peaks in predicting malignant and benign breast lesions using the area under the receiver operating characteristic curve (AUC). The results showed a good capacity to predict malignant breast lesions for hepcidin-25 [AUC: 0.82; 95% confidence interval (CI) 0.75-0.90] and ferritin light chain (AUC: 0.86; 95% CI 0.79-0.92). Conversely, a weak and satisfactory capability to predict benign breast lesion was observed for hepcidin-25 (AUC: 0.63; 95% CI 0.41-0.85) and ferritin light chain (AUC: 0.73; 95% CI 0.49-0.97). A significant association between HER2 status and hepcidin-25 was observed and the distribution of transferrin and ferritin were found significantly different in patients with breast cancer when compared with that of controls.This study provides evidence that hepcidin and ferritin light chain level in plasma may be of clinical usefulness to predict malignant and benign disease with respect to healthy controls.