Alberto Mantovani

Tumor-associated macrophages (TAM). Demonstration in the late ‘70s of the protumor function of tumor-associated macrophages (TAM, an acronym coined by him) linking inflammation and cancer (Bottazzi et al, Science 1983; reviewed in Balkwill and Mantovani, Lancet, 2001). TAM as an M2-like population (Mantovani et al., Nature 2008; Balkwill et al., Cancer Cell 2005). Promotion of tumor progression by IL-1 (Cancer Res. 1990; 1993). First 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). Role of PTX3 and Complement in macrophage-driven tumor promoting inflammation (Bonavita et al Cell 2015; Magrini et al Nature Cancer 2019). Discovery of a novel pathway of anti-tumor immunity involving neutrophils, macrophages and unconventional, double negative T cells (Ponzetta et al, Cell 2019). 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. 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/ ACKR2 as a decoy receptor for inflammatory CC chemokines (Mantovani et al, Nature Rev. Immunol 2006). Role of chemokines in carcinogenesis (e.g. Bonavita et al Cell 2015). 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 IL-1 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 in 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; 2019). Role in carcinogenesis. In NK cells IL-1R8 serves as a checkpoint: its blocking unleashes resistance to carcinogenesis and metastasis at selected anatomical sites (Molgora et al, Nature 2017).