Paola Allavena

University of Milan, Milano, Lombardy, Italy

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Publications (266)1481.96 Total impact

  • Source
    Gastroenterology 04/2015; 148(4):S-1122. DOI:10.1016/S0016-5085(15)33824-5 · 13.93 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 · 13.91 Impact Factor
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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; 17:38–44. DOI:10.1016/j.coph.2014.07.004 · 4.23 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 · 2.50 Impact Factor
  • Pancreatology 06/2014; 14(3):S66. DOI:10.1016/j.pan.2014.05.604 · 2.50 Impact Factor
  • Pancreatology 06/2014; 14(3):S71. DOI:10.1016/j.pan.2014.05.619 · 2.50 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-276. DOI:10.1016/S0016-5085(14)60973-2 · 13.93 Impact Factor
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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 www.bjcancer.com.
    British Journal of Cancer 04/2014; 111(4). DOI:10.1038/bjc.2014.149 · 4.82 Impact Factor
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    ABSTRACT: Purpose. Tumor infiltrating T lymphocytes (TILs) play a key role in the clinical outcome of human colo-rectal cancer (CRC); however, the dynamics of their recruitment along CRC 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 stage II and III CRC patients. The role of TLT in lymphocyte recruitment was assessed in a preclinical model of CRC. Results. In both human colo-rectal cancer and in a murine model of CRC, 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 stage II CRC patients. Conclusions. We provide evidence that tertiary lymphoid tissue is associated to lymphocyte infiltration in CRC, providing a pathway of recruitment for TILs. TLT cooperates with TILs in a coordinated anti-tumor immune response, when identifying low risk early-stage CRC patients, thus representing a novel prognostic biomarker for CRC.
    Clinical Cancer Research 02/2014; 20(8). DOI:10.1158/1078-0432.CCR-13-2590 · 8.19 Impact Factor
  • The Lancet 02/2014; 383:S106. DOI:10.1016/S0140-6736(14)60369-X · 45.22 Impact Factor
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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 · 3.51 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 · 5.01 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 · 4.82 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; DOI:10.1016/j.cyto.2013.07.024 · 2.87 Impact Factor
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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 · 6.28 Impact Factor
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    ABSTRACT: Inflammation is now a well-recognized hallmark of cancer progression. Tumor-associated macrophages (TAMs) are one of the major inflammatory cells that infiltrate murine and human tumors. While epidemiological studies indicate a clear correlation between TAM density and poor prognosis in a number of human cancers, transgenic studies and transcriptome profiling of TAMs in mice have established their crucial role in cancer progression. In fact, TAMs affect diverse aspects of cancer progression including tumor cell growth and survival, invasion, metastasis, angiogenesis, inflammation, and immunoregulation. New evidences have extended the repertoire of these cells to other tumor promoting activities like interactions with cancer stem cells, response to chemotherapy, and tumor relapse. These findings have triggered efforts to target TAMs and their associated molecules to modulate tumor progression. In particular, "re-education" to activate their anti-tumor potential or elimination of tumor promoting TAMs are strategies undergoing preclinical and clinical evaluation. Proof-of-principle studies indicate that TAM-centered therapeutic strategies may contribute to cancer therapy.
    Seminars in Immunopathology 05/2013; 35(5). DOI:10.1007/s00281-013-0367-7 · 6.48 Impact Factor
  • Pancreatology; 05/2013
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    Oncotarget 04/2013; 4(4):496-7. · 6.63 Impact Factor
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    ABSTRACT: Aim: Recent experimental studies have suggested that chemokines, a subclass of chemoattractant cytokines which play an important role in regulating leukocyte migration and intercellular communication, participate in brain responses of traumatic injury. Fractalkine (CX3CL1) is a peculiar chemokine, the only one with a CX3C motif, existing both as a soluble and a membrane-anchored molecule. In the brain, Fractalkine has been suggested to have a role in neuroprotection under experimental conditions of brain injury. Methods: Eighteen human brain samples were obtained during surgery of decompressive craniotomy for severe traumatic brain injury (TBI) or after spontaneous intracranial haemorrhage (ICH). Five normal brain samples were obtained during surgery for unruptured intracranial aneurysms (standard gyrectomy). Immunohistochemistry of formalin fixed and paraffin embedded tissues was performed in order to verify the expression of fractalkine and its receptor (CX3CR1). The values of chemokine and receptor expression were correlated with the clinical parameters of the patients. Results: The chemokine fractalkine was significantly upregulated in the neural compartment after brain injury, compared to normal brain samples. Intensity scores were significantly higher when the interval between injury and surgery was >5 h, (P=0.015). In the glial compartment, Fractalkine expression was significantly associated with less severe clinical conditions and lower intracranial pressure at surgery (P=0.014). Expression of the receptor CX3CR1 was detected, at low intensity, on both glial and neurons. Higher expression in neurons was associated with better clinical conditions (Glasgow score) of patients at admission (P=0.037). Conclusion: The results of this study highlights for the first time that fractalkine and its receptor CX3CR1 are expressed in the human brain after TBI and ICH and may be involved in the limitation of tissue damage.
    Journal of neurosurgical sciences 03/2013; 57(1):55-62. · 0.78 Impact Factor

Publication Stats

25k Citations
1,481.96 Total Impact Points

Institutions

  • 1991–2015
    • University of Milan
      • • Department of Medical Biotechnology and Translational Medicine
      • • Faculty of Medicine
      Milano, Lombardy, Italy
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
  • 2006–2014
    • Istituto Clinico Humanitas IRCCS
      • Department of Immunology and Inflammation
      Milano, Lombardy, Italy
  • 2009
    • Amedeo Avogadro University of Eastern Piedmont
      • Department of Pharmaceutical Sciences
      Alessandria, Piedmont, Italy
  • 2008
    • Kagawa University
      Takamatu, Kagawa, Japan
  • 1980–2008
    • Mario Negri Institute for Pharmacological Research
      • Department of Oncology
      Milano, Lombardy, Italy
  • 2003–2006
    • San Raffaele Scientific Institute
      Milano, Lombardy, Italy
  • 2005
    • IEO - Istituto Europeo di Oncologia
      • Department of Experimental Oncology
      Milano, Lombardy, Italy
  • 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
  • 1987
    • CUNY Graduate Center
      New York, New York, United States
  • 1986
    • Ospedali Riuniti di Bergamo
      • Department of Hematology
      Bérgamo, Lombardy, Italy
    • National Institutes of Health
      • Laboratory of Molecular Pharmacology
      Maryland, United States
  • 1983–1985
    • National Cancer Institute (USA)
      Maryland, United States