Cellular and Humoral Innate Immunity Lab

The challenge

We know that macrophages have the potential to kill cancer cells, to produce vascular damage – that can further drive tumor necrosis – and to activate other innate and adaptive anti-tumor mechanisms. However, in many types of cancer, researchers have shown that macrophages can also contribute to cancer progression and metastasis, either by directly supporting cancer cells and nurturing the tumor microenvironment (TEM), or by suppressing the immune response. This double identity of macrophages depends on the innate humoral molecular cues collected by these cells in the TEM: by studying these cues we can hope to leverage them to fight cancer and to better control immune responses to insults and infections.

Main research areas

Tumor-associated macrophages

Studying macrophages infiltrating mouse metastatic tumors and human tumors, Prof. Mantovani was one of the first scientists to demonstrate the existence of tumor-associated macrophages (TAM, an acronym now generally used and coined by him in the 70’s) linking inflammation and cancer (Lancet, 2001). He also led the first proof of principle that targeting tumor promoting macrophages has therapeutic value in humans (Cancer Cell, 2013). Mantovani’s group and demonstrated pentraxin PTX3 role as an extrinsic oncosuppressor in murine and human tumors, regulating the complement and macrophage-driven tumor-promoting inflammation (Cell, 2015). More recently, Mantovani contributed to the discovery of a novel pathway of anti-tumor immunity involving neutrophils, macrophages and unconventional, double negative T cells (Cell, 2019).

Chemokines

This interest in the role of innate immunity in cancer has developed into the dissection of what we now call cytokines and molecular pathways of innate immunity. For instance, the view that macrophages promote cancer allowed scientists, in the early ‘80s, to search for macrophage attractants (now called chemokines) produced by cancer cells: Mantovani’s group described the role in TAM recruitment of a unique monocyte attractant, Monocyte Chemotactic Protein-1 (CCL2), as tumor-derived chemotactic factor (Science, 1983). He discovered that IL-6 induces chemokine production in endothelial cells, contributing to leukocyte recruitment on-site, a key component of the relationship between inflammation and cancer (Immunity, 1997). During his career, Mantovani contributed to the characterization of chemokines role in pathophysiology, including dendritic cell and polarized T cell migration (see Nature Reviews Immunology, 2006).

IL-1 and Toll-like receptors

Mantovani’s group identification of the type II IL-1 receptor as a decoy receptor, a novel concept in biology, represented a paradigm shift after the original definition of the concept of “receptor” by Langley in the 1930s (Science, 1993). Decoy receptors are now recognized as a general, evolutionary conserved strategy to tune cytokines, chemokines and growth factors. Mantovai’s lab also discovered that MYD88 is the adaptor molecule downstream of mammalian TLR, a finding with broad impact (Muzio et al, JEM) and performed the cloning and characterization of IL-1R8, a negative regulator of IL-1 receptor and TLR signaling (Immunity, 2013), which was followed by the demonstrating that in NK cells IL-1R8 serves as a checkpoint: its blocking unleashes resistance to carcinogenesis and metastasis at selected anatomical sites (Nature, 2017).

Humoral innate immunity

Mantovani did the structural and functional characterization, as well as cloning, of the first long pentraxin PTX3 as an IL-1 inducible gene (Nature, 2002) demonstrating its role as a paradigm for humoral innate immunity. The molecule is now in the process of diagnostic and therapeutic translation to the clinic (NEJM, 2014). As a regulator of macrophage-driven tumor promoting inflammation (Cell, 2015), PTX3 is a bona fide cancer gene, silenced in selected human tumors such as colorectal cancer, a finding now independently confirmed in large patients’ cohorts. PTX3 emerged also as a strong prognostic biomarker in COVID-19 (Nature Immunology, 2021).