Paola Allavena

University of Milan, Milano, Lombardy, Italy

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Publications (273)1422.13 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: There is a well-established link between inflammation and cancer of various organs, but little data is available on inflammation-associated markers of diagnostic and prognostic clinical utility in pulmonary malignancy. Blood samples were prospectively collected from 75 resectable lung cancer patients before surgery and in a cohort of 1358 high-risk subjects. Serum levels of long pentraxin 3 (PTX3) were determined by high sensitivity ELISA. PTX3 immunostaining was evaluated by immunohistochemistry in cancer tissue. Serum PTX3 levels in the high-risk population were not predictive of developing subsequent lung cancer or any other malignancy; however serum PTX3 values in patients with lung cancer were significantly higher compared with cancer-free heavy smokers. With a cut-off of 4.5 ng/ml, specificity was 0.80, sensitivity 0.69, positive predictive value 0.15 and negative predictive value 0.98. The Receiver Operating Curve (ROC) for serum PTX3 had an area under the curve (AUC) of 83.52%.Preoperative serum PTX3 levels in lung cancer patients did not correlate with patient outcome, but high interstitial expression of PTX3 in resected tumor specimens was a significant independent prognostic factor associated with shorter survival (p<0.001).These results support the potential of serum PTX3 as a lung cancer biomarker in high-risk subjects.Furthermore, PTX3 immunohistochemistry findings support the role of local inflammatory mechanisms in determining clinical outcome and suggest that local expression of PTX3 may be of prognostic utility in lung cancer patients. This article is protected by copyright. All rights reserved.
    International Journal of Cancer 08/2015; DOI:10.1002/ijc.29822 · 5.09 Impact Factor
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    Antonio Sica · Marco Erreni · Paola Allavena · Chiara Porta
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    ABSTRACT: Macrophages are cells of the innate immunity constituting the mononuclear phagocyte system and endowed with remarkable different roles essential for defense mechanisms, development of tissues, and homeostasis. They derive from hematopoietic precursors and since the early steps of fetal life populate peripheral tissues, a process continuing throughout adult life. Although present essentially in every organ/tissue, macrophages are more abundant in the gastro-intestinal tract, liver, spleen, upper airways, and brain. They have phagocytic and bactericidal activity and produce inflammatory cytokines that are important to drive adaptive immune responses. Macrophage functions are settled in response to microenvironmental signals, which drive the acquisition of polarized programs, whose extremes are simplified in the M1 and M2 dichotomy. Functional skewing of monocyte/macrophage polarization occurs in physiological conditions (e.g., ontogenesis and pregnancy), as well as in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer) and is now considered a key determinant of disease development and/or regression. Here, we will review evidence supporting a dynamic skewing of macrophage functions in disease, which may provide a basis for macrophage-centered therapeutic strategies.
    Cellular and Molecular Life Sciences CMLS 07/2015; DOI:10.1007/s00018-015-1995-y · 5.81 Impact Factor
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    ABSTRACT: Tumour-associated macrophages (TAMs) play key roles in tumour progression. Recent evidence suggests that TAMs critically modulate the efficacy of anticancer therapies, raising the prospect of their targeting in human cancer. In a large retrospective cohort study involving 110 patients with pancreatic ductal adenocarcinoma (PDAC), we assessed the density of CD68-TAM immune reactive area (%IRA) at the tumour-stroma interface and addressed their prognostic relevance in relation to postsurgical adjuvant chemotherapy (CTX). In vitro, we dissected the synergism of CTX and TAMs. In human PDAC, TAMs predominantly exhibited an immunoregulatory profile, characterised by expression of scavenger receptors (CD206, CD163) and production of interleukin 10 (IL-10). Surprisingly, while the density of TAMs associated to worse prognosis and distant metastasis, CTX restrained their protumour prognostic significance. High density of TAMs at the tumour-stroma interface positively dictated prognostic responsiveness to CTX independently of T-cell density. Accordingly, in vitro, gemcitabine-treated macrophages became tumoricidal, activating a cytotoxic gene expression programme, inhibiting their protumoural effect and switching to an antitumour phenotype. In patients with human PDAC, neoadjuvant CTX was associated to a decreased density of CD206+ and IL-10+ TAMs at the tumour-stroma interface. Overall, our data highlight TAMs as critical determinants of prognostic responsiveness to CTX and provide clinical and in vitro evidence that CTX overall directly re-educates TAMs to restrain tumour progression. These results suggest that the quantification of TAMs could be exploited to select patients more likely to respond to CTX and provide the basis for novel strategies aimed at re-educating macrophages in the context of CTX.
    Gut 07/2015; DOI:10.1136/gutjnl-2015-309193 · 14.66 Impact Factor
  • Giulia Marelli · Paola Allavena · Marco Erreni
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    Gastroenterology 04/2015; 148(4):S-1122. DOI:10.1016/S0016-5085(15)33824-5 · 16.72 Impact Factor
  • Alberto Mantovani · Paola Allavena
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    ABSTRACT: Macrophages are essential components of the inflammatory microenvironment of tumors. Conventional treatment modalities (chemotherapy and radiotherapy), targeted drugs, antiangiogenic agents, and immunotherapy, including checkpoint blockade, all profoundly influence or depend on the function of tumor-associated macrophages (TAMs). Chemotherapy and radiotherapy can have dual influences on TAMs in that a misdirected macrophage-orchestrated tissue repair response can result in chemoresistance, but in other circumstances, TAMs are essential for effective therapy. A better understanding of the interaction of anticancer therapies with innate immunity, and TAMs in particular, may pave the way to better patient selection and innovative combinations of conventional approaches with immunotherapy. © 2015 Mantovani and Allavena.
    Journal of Experimental Medicine 03/2015; 212(4). DOI:10.1084/jem.20150295 · 12.52 Impact Factor
  • Alberto Mantovani · Annunciata Vecchi · Paola Allavena
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    ABSTRACT: Mononuclear phagocytes are major players in diverse pathological conditions which include chronic inflammatory diseases, infection, autoimmunity, atherosclerosis, metabolic disorders, and cancer. Plasticity is a fundamental property of cells of the monocyte–macrophage lineage and a variety of modulators profoundly affect monocytes and macrophages. Tumor-associated macrophages (TAMs) provide a paradigm for macrophage plasticity and anticancer therapeutic modalities (chemotherapy, radiotherapy, and immunotherapy) profoundly affect their function. The development of innovative strategies targeting cells of the monocyte–macrophage lineage may pave the way to innovative therapies for a wide range of diseases.
    Current Opinion in Pharmacology 08/2014; 17(1):38–44. DOI:10.1016/j.coph.2014.07.004 · 4.60 Impact Factor
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    ABSTRACT: Targeted therapies were rationally designed to inhibit molecular pathways in tumor cells critically involved in growth and survival; however, many drugs used in targeted therapies may affect the immune system. In addition, selected conventional chemotherapeutic agents have also been reported to be endowed with direct or indirect effects on immunity, for instance via immunogenic death of tumors. Thus, cancer therapies may have off-target effects, some of which are directed to the immune system. Here, we will review some of these effects in specific therapeutic approaches. We will examine the modulation of the immune contexture in human sarcoma and melanoma induced by anti-angiogenic therapies and by BRAF inhibitors, respectively. We will then discuss how the anti-tumor agent trabectedin is selectively cytotoxic to cells of the monocytic-macrophage lineage and how these immune-related effects can be part of the response to treatment.
    Cancer Immunology and Immunotherapy 07/2014; 64(1). DOI:10.1007/s00262-014-1576-1 · 3.94 Impact Factor
  • Pancreatology 06/2014; 14(3):S8. DOI:10.1016/j.pan.2014.05.405 · 2.84 Impact Factor
  • Pancreatology 06/2014; 14(3):S66. DOI:10.1016/j.pan.2014.05.604 · 2.84 Impact Factor
  • Pancreatology 06/2014; 14(3):S71. DOI:10.1016/j.pan.2014.05.619 · 2.84 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-276. DOI:10.1016/S0016-5085(14)60973-2 · 16.72 Impact Factor
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    M D'Incalci · N Badri · C M Galmarini · P Allavena
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    ABSTRACT: Trabectedin is the first marine-derived anti-neoplastic drug approved for the treatment of advanced soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for the treatment of patients with relapsed platinum-sensitive ovarian cancer. From the beginning of its development, trabectedin showed some peculiar properties that clearly distinguished it from other anti-cancer drugs. In this mini-review, we will outline the current state of knowledge regarding the mode of action of trabectedin, which appears to represent a new class of anti-neoplastic drugs acting both on cancer cells and on the tumour microenvironment.British Journal of Cancer advance online publication 22 April 2014; doi:10.1038/bjc.2014.149
    British Journal of Cancer 04/2014; 111(4). DOI:10.1038/bjc.2014.149 · 4.84 Impact Factor
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    ABSTRACT: Purpose: Tumor-infiltrating T lymphocytes (TIL) play a key role in the clinical outcome of human colorectal cancer; however, the dynamics of their recruitment along colorectal cancer clinical progression have not been fully elucidated. Tertiary lymphoid tissue (TLT) is an ectopic organized lymph node-like structure that typically forms at sites of chronic inflammation and is involved in adaptive immune responses. Its occurrence in cancer is sporadically documented and its role and clinical relevance is largely unknown. Experimental design: The occurrence of TLT, the correlation with TILs, and the clinical relevance were evaluated retrospectively, in a cohort study involving a consecutive series of 351 patients with stage II and III colorectal cancer. The role of TLT in lymphocyte recruitment was assessed in a preclinical model of colorectal cancer. Results: In both human colorectal cancer and in a murine model of colorectal cancer, we identified organized TLT, highly vascularized (including high endothelial venules), and correlated with the density of CD3(+) TILs. Intravenous injection in mice of GFP splenocytes resulted in homing of lymphocytes to TLT, suggesting an active role of TLT in the recruitment of lymphocytes to tumor areas. Accordingly, TLT density and TIL infiltration correlated and were coordinated in predicting better patient's outcome among patients with stage II colorectal cancer. Conclusions: We provide evidence that TLT is associated with lymphocyte infiltration in colorectal cancer, providing a pathway of recruitment for TILs. TLT cooperates with TILs in a coordinated antitumor immune response, when identifying patients with low-risk early-stage colorectal cancer, thus, representing a novel prognostic biomarker for colorectal cancer.
    Clinical Cancer Research 02/2014; 20(8). DOI:10.1158/1078-0432.CCR-13-2590 · 8.72 Impact Factor
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a disease with dismal prognosis and is invariably diagnosed late. Tests used to diagnose or monitor the disease are invasive, inaccurate, and expensive. Tumour-supportive stroma is an important feature of PDAC. All-trans retinoic acid renders activated stellate cells quiescent and thereby targets cancer and immune cells in cancer as shown by our laboratory. PTX3 gene level expression is downregulated on rendering stellate cells quiescent. We aimed to investigate the role of PTX3 in PDAC and to assess it as a marker for pancreatic cancer.
    The Lancet 02/2014; 383:S106. DOI:10.1016/S0140-6736(14)60369-X · 45.22 Impact Factor
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    Carlos M Galmarini · Maurizio D'Incalci · Paola Allavena
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    ABSTRACT: The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc.) all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment.
    Marine Drugs 02/2014; 12(2):719-33. DOI:10.3390/md12020719 · 2.85 Impact Factor
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    ABSTRACT: This study: i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared to trabectedin in cell lines deficient in specific mechanisms of repair, ii) evaluated their in vivo antitumor activity against a series of murine tumours and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumour lines were very similar. Nucleotide Excision Repair (NER) deficient cells were ~4-fold more resistant to trabectedin, lurbinectedin and Zalypsis®. Cells deficient in Non-Homologous End Joining (NHEJ), MRN complex and Translesion Synthesis (TLS) were slightly more sensitive to the three compounds (~ 5-fold) while cells deficient in Homologous Recombination (HR) were markedly more sensitive (150-200-fold). All three compounds showed a good antitumor activity in several in vivo models. Lurbinectedin and trabectedin had a similar pattern of antitumor activity in murine tumours and in xenografts, whereas Zalypsis® appeared to have a distinct spectrum of activity. The fact that no relationship whatsoever was found between the in vitro cytotoxic potency and the in vivo antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host-mediated effects are involved in the in vivo pharmacological effects. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 11/2013; 133(9). DOI:10.1002/ijc.28213 · 5.09 Impact Factor
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    ABSTRACT: Background: In pancreatic ductal adenocarcinoma (PDAC), fractalkine receptor CX3CR1 contributes to perineural invasion (PNI). We investigated whether CX3CR1 expression occurs early in PDAC and correlates with tumour features other than PNI. Methods: We studied CX3CR1 and CX3CL1 expression by immunohistochemistry in 104 human PDAC and coexisting Pancreatic Intraepithelial Neoplasia (PanIN), and in PdxCre/LSL-KrasG12D mouse model of PDAC. CX3CR1 expression in vitro was studied by a spheroid model, and in vivo by syngenic mouse graft of tumour cells. Results: In total, 56 (53.9%) PDAC expressed CX3CR1, 70 (67.3%) CX3CL1, and 45 (43.3%) both. CX3CR1 expression was independently associated with tumour glandular differentiation (P=0.005) and PNI (P=0.01). Pancreatic Intraepithelial Neoplasias were more frequently CX3CR1+ (80.3%, P<0.001) and CX3CL1+ (86.8%, P=0.002) than matched cancers. The survival of PDAC patients was better in those with CX3CR1+ tumour (P=0.05). Mouse PanINs were also CX3CR1+ and -CL1+. In vitro, cytokines significantly increased CX3CL1 but not CX3CR1 expression. Differently, CX3CR1 was upregulated in tumour spheroids, and in vivo only in well-differentiated tumours. Conclusion: Tumour differentiation, rather than inflammatory signalling, modulates CX3CR1 expression in PanINs and PDAC. CX3CR1 expression pattern suggests its early involvement in PDAC progression, outlining a potential target for interfering with the PanIN transition to invasive cancer.
    British Journal of Cancer 10/2013; 109(9). DOI:10.1038/bjc.2013.565 · 4.84 Impact Factor
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    ABSTRACT: Tumor microenvironment inflammatory cells play a major role in cancer progression. Among these, the Tumor Associated Macrophages (TAMs) infiltration depends on the kind of chemokine, cytokines and growth factors secreted by the tumor cells and by the stroma in response to the cancer invasion. TAMs have been found to promote anti-tumor response in early stages and to stimulate neovascularization and metastases in advanced disease. In the microenvironment chemo-attractants of many human cancers, MIF and VEGF correlate with an increased TAMs recruitment. In addition, MIF enhances tumor cells metastases by modulating the immune responses and by promoting the angiogenesis related to VEGF. On the contrary the inhibition of MIF can lead to cell cycle arrest and apoptosis. Some chemokines (e.g. CXCL12, CXCL11, CXCL8) and their receptors, thanks to their ability to modulate migration and proliferation, are involved in the angiogenetic process. In this study we compared the expression of MIF mRNA with VEGF mRNA expression and with mRNA expression of other chemokines related to neo-angiogenesis, such as CXCL12, CXCL11, CXCL8 and CXCR4, in human endometrial cancer tissue (EC) and normal endometrium (NE). Fresh samples of EC tissue and NE were extracted from 15 patients with FIGO stage I-III undergoing primary surgery. Some of the tissue was sent for histology and part of it was treated with RNA later and stored at -80°C. Four patients dropped out. A significant up-regulation of MIF mRNA in EC tissue versus NE samples (P=0.01) was observed in all 11 patients. The MIF mRNA over-expression was coincident with a VEGF mRNA overexpression in 54% of patients (P=NS). MIF mRNA was inversely related to CXCL12 mRNA expression (P=0.01). MIF over-expression was significantly related to low grading G1-2 (P=0.01), endometrial type I (P=0.05), no lymphovascular spaces invasion (P=0.01) and 3years DFS (P=0.01). As reported in previous studies on patients with breast cancer, our data suggest that the up-regulation of MIF in patients with endometrial cancer might be related to the inhibition of distant and lymphatic spread.
    Cytokine 08/2013; 64(2). DOI:10.1016/j.cyto.2013.07.024 · 2.66 Impact Factor
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    Article: Trabectedin
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    ABSTRACT: Tumor-associated macrophages (TAMs) and other myeloid cells that infiltrate neoplastic lesions promote tumor progression and are associated with poor patient prognosis. We have recently demonstrated that trabectedin, a licensed and commercially available anticancer agent, is selectively cytotoxic for TAMs and their circulating precursors (monocytes). The macrophage-depleting effect of trabectedin is a key component of its antitumor activity.
    OncoImmunology 06/2013; 2(6):e24614. DOI:10.4161/onci.24614 · 6.27 Impact Factor

Publication Stats

25k Citations
1,422.13 Total Impact Points


  • 1991–2015
    • University of Milan
      • Department of Medical Biotechnology and Translational Medicine
      Milano, Lombardy, Italy
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
  • 2006–2014
    • Istituto Clinico Humanitas IRCCS
      • Department of Immunology and Inflammation
      Rozzano, Lombardy, Italy
  • 1980–2013
    • Mario Negri Institute for Pharmacological Research
      • Department of Oncology
      Milano, Lombardy, Italy
  • 2011
    • University of California, San Francisco
      San Francisco, California, United States
  • 2008
    • Kagawa University
      Takamatu, Kagawa, Japan
  • 2005
    • San Raffaele Scientific Institute
      Milano, Lombardy, Italy
    • IEO - Istituto Europeo di Oncologia
      • Department of Experimental Oncology
      Milano, Lombardy, Italy
  • 2002
    • Università degli Studi di Milano-Bicocca
      Milano, Lombardy, Italy
    • Regional Hospital Heilig Hart
      Louvain, Flanders, Belgium
  • 2000–2001
    • Università degli Studi di Brescia
      • Department of Clinical and Experimental Sciences
      Brescia, Lombardy, Italy
  • 1997
    • University of Leuven
      • Department of Microbiology and Immunology
      Louvain, Flemish, Belgium
  • 1990
    • Ospedali Riuniti di Bergamo
      • Department of Hematology
      Bérgamo, Lombardy, Italy
  • 1987
    • CUNY Graduate Center
      New York, New York, United States
  • 1985–1986
    • National Institutes of Health
      • Laboratory of Molecular Pharmacology
      Maryland, United States
  • 1983–1985
    • National Cancer Institute (USA)
      Maryland, United States