Alberto Mantovani

• Tumor biology.  Demonstration in the late ‘70s of the protumor function of tumor-associated macrophages  (TAM, an acronym now generally used and coined by him in the ‘70s)  linking inflammation and cancer (reviewed in Balkwill and Mantovani, Lancet, 2001). TAM as a prototypic M2-like population (Mantovani et al., Nature 2008; Balkwill et al., Cancer Cell 2005).  First molecular linking of a genetic event (RET/PTC rearrangement)  causing cancer in humans to the construction of an inflammatory microenvironment (Borrello et al., PNAS 2005). Proof of principle that targeting tumor promoting macrophages has therapeutic value in humans (Germano et al, Cancer Cell 2013). Demonstration that PTX3 is an extrinsic oncosuppressor regulating Complement and macrophage driven tumor promoting inflammation (Bonavita et al Cell 2015). Alberto Mantovani is recognized among his peers as a forerunner in the ‘70s and a “founding father” of the renaissance of the inflammation-cancer connection.
• Chemokines. Original description and role in TAM recruitment of a unique monocyte attractant, Monocyte Chemotactic  Protein-1 (CCL2), as tumor-derived chemotactic factor (Bottazzi et al, Science 1983). Characterization of chemokines and role in pathophysiology, including dendritic cell and polarized T cell migration. Induction of chemokine production by IL-6 in endothelial cells via trans-signaling, a key component of chronic inflammation and cancer (Romano et al, Immunity 1997). Characterization of D6 as a decoy receptor for inflammatory CC chemokines (Mantovani et al, Nature Rev. Immunol 2006). Role of chemokines in carcinogenesis (for a recent contribution Bonavita et al Cell 2015).  Role of the chemokines vMIPs in attracting Th2 cells and role of D6 (ACKR2) in Kaposi’s sarcoma.
• IL-1/Toll-like receptors (TLR). Endothelial cell activation by IL-1 and cytokines (Rossi et al., Science 1985; Bussolino et al, Nature 1989; Romano et al, Immunity 1997). Identification of the type II receptor as a decoy receptor, a novel concept in biology (Colotta et al, Science 1993); the discovery of a decoy receptor represented a paradigm shift after the original definition of the concept of “receptor” by Langley at the 1930’; decoy receptors are now recognized as a general,  evolutionary conserved strategy to tune cytokines, chemokines and growth factors. Cloning of an intracellular isoform of the IL-1 receptor antagonist (Muzio et al., J. Exp. Med.  1995). First demonstration of MyD88 as the adaptor of mammalian Toll-Like Receptors (TLR) and identification of downstream transducers (Muzio et al., J. Exp. Med. 1998). Cloning and characterization of TIR8/SIGIRR (IL-1R8), a negative regulator of IL-1 receptor and TLR signalling (Garlanda, et al, Immunity 2013). Role in carcinogenesis.
• Humoral innate immunity: cloning (cDNA and genomic, mouse and human), structural and functional characterization of the first long pentraxin PTX3 as an IL-1 inducible gene (Garlanda et al, Nature 2002; Jeannin et al, Immunity 2005; Jaillon et al. J. Exp Med 2007 ; Deban et al, Nature Immunol. 2010; Jaillon et al. Immunity 2014; Bonavita et al. Cell 2015); structural immunobiology; role as a paradigm for humoral innate immunity; role as an extrinsic oncosuppresor in murine and human tumors regulating Complement and macrophage driven tumor promoting inflammation (Bonavita et al. Cell 2015); diagnostic and therapeutic translation (Cunha et al New England J. Med. 2014; ongoing). Thus, a regulator of macrophage-driven tumor promoting inflammation is a bona fide cancer gene, silenced in selected human tumors such as colorectal cancer, a finding now independently confirmed.

Originals

1. Bonavita E, Gentile S, Rubino M, Maina V, Papait R, Kunderfranco P, Greco C, Feruglio F, Molgora M, Laface I, Tartari S, Doni A, Pasqualini F, Barbati E, Basso G, Galdiero MR, Nebuloni M, Roncalli M, Colombo PG, Laghi L, Lambris JD, Jaillon S, Garlanda C, Mantovani A. – PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160: 700-714, 2015.

Reviews

1. Mantovani A., Marchesi F., Laghi L., Malesci A., Allavena P.  – Tumor-associated macrophages as treatment targets in oncology. Nature Rev, Clin. Oncol.;  adv. online publication 2017 doi: 10.1038/nrclinonc.2016.217
2. Sica A, Mantovani A. – Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 122: 787-795, 2012.
3. Mantovani A, Allavena P, Sica A, Balkwill F – Cancer-Related Inflammation. Nature 454: 436-444, 2008.
4. Mantovani, A., Romero, P., Paluka, AK., Marincola, FM. – Tumor immunity: effector response to tumor and the influence of the microenvironment. Lancet 371:771-783, 2008.