PTX3 acts as an extrinsic oncosuppressor.

Inflammation is an essential component of the tumor microenvironment that sustains tumor development and growth [1]. The role in cancer-related inflammation of innate immunity cells recruited in the tumor has been clarified in preclinical models. In contrast, the role of the humoral arm of the innate immune system, which includes biochemically heterogeneous molecules such as Complement components, collectins, ficolins and pentraxins, is still under investigated. The long pentraxin PTX3 represents a functional paradigm of humoral innate immunity [2]. By interacting with selected microbial moieties and playing opsonic activity via Fcγ receptors, and activating and regulating the Complement cascade, PTX3 acts as a functional ancestor of antibodies. PTX3 plays non-redundant roles in resistance against selected microbial pathogens and in regulating inflammatory and tissue repair responses [2, 3]. PTX3 is highly conserved in evolution and genetic evidence is consistent with a role of PTX3 in antimicrobial resistance in humans [3, 4]. We have recently investigated the role of the humoral arm of innate immunity in cancer-related inflammation using the long pentraxin PTX3 as a paradigm [5]. We found that PTX3-deficiency in mice caused increased susceptibility to mesenchymal and epithelial carcinogenesis in the models of 3-Methylcholanthrene (3-MCA)-induced carcinogenesis, and 7,12-dimethylbenz [α] anthracene/terephthalic acid (DMBA/TPA)-induced skin carcinogenesis. In these models, infiltrating leukocytes, in particular cells of the monocyte-macrophage lineage, and endothelial cells were a major source of PTX3 in response to locally produced IL-1, and both contributed to PTX3-dependent protection against carcinogenesis. PTX3-deficiency was associated with enhanced macrophage tumor infiltration, pro-inflammatory cytokine production, angiogenesis, complement C3 deposition and C5a levels, suggesting exacerbated cancer-related inflammation, whereas PTX3 had no direct effect on tumor cell proliferation. We further showed that genetic inactivation of C3 reverted the increased susceptibility to 3-MCA-induced carcinogenesis and macrophage recruitment and demonstrated that PTX3 regulated C3-deposition on sarcoma cells by interacting with and recruiting the negative regulator Factor H. In addition, CCL2-inibition was sufficient to revert the increased susceptibility of PTX3-deficent mice to 3-MCA and the M2-like phenotype of tumor-associated macrophages. Editorial