Cecilia Garlanda

Occurrence and significance of tumor-associated neutrophils in patients with colorectal cancer.

Inflammatory cells are an essential component of the tumor microenvironment. Neutrophils have emerged as important players in the orchestration and effector phase of innate and adaptive immunity. The significance of tumor‐associated neutrophils (TAN) in colorectal cancer (CRC) has been the subject of conflicting reports and the present study was designed to set up a reliable methodology to assess TAN infiltration in CRC and to evaluate their clinical significance. CD66b and myeloperoxidase (MPO) were assessed as candidate neutrophil markers in CRC using immunohistochemistry. CD66b was found to be a reliable marker to identify TAN in CRC tissues, whereas MPO also identified a subset of CD68+ macrophages. CRC patients (nu2009=u2009271) (Stages I–IV) were investigated retrospectively by computer‐assisted imaging on whole tumor sections. TAN density dramatically decreases in Stage IV patients as compared to Stage I–III. At Cox analysis, higher TAN density was associated with better prognosis. Importantly, multivariate analysis showed that prognostic significance of TAN can be influenced by clinical stage and 5‐fluorouracil(5‐FU)‐based chemotherapy. On separate analysis of Stage III patients (nu2009=u2009178), TAN density had a dual clinical significance depending on the use of 5‐FU‐based chemotherapy. Unexpectedly, higher TAN density was associated with better response to 5‐FU‐based chemotherapy. Thus, TAN are an important component of the immune cell infiltrate in CRC and assessment of TAN infiltration may help identify patients likely to benefit from 5‐FU‐based chemotherapy. These results call for a reassessment of the role of neutrophils in cancer using rigorous quantitative methodology.

IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity

Interleukin-1 receptor 8 (IL-1R8, also known as single immunoglobulin IL-1R-related receptor, SIGIRR, or TIR8) is a member of the IL-1 receptor (ILR) family with distinct structural and functional characteristics, acting as a negative regulator of ILR and Toll-like receptor (TLR) downstream signalling pathways and inflammation. Natural killer (NK) cells are innate lymphoid cells which mediate resistance against pathogens and contribute to the activation and orientation of adaptive immune responses. NK cells mediate resistance against haematopoietic neoplasms but are generally considered to play a minor role in solid tumour carcinogenesis. Here we report that IL-1R8 serves as a checkpoint for NK cell maturation and effector function. Its genetic blockade unleashes NK-cell-mediated resistance to hepatic carcinogenesis, haematogenous liver and lung metastasis, and cytomegalovirus infection.

The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells

Cerutti and collaborators show that the humoral arms of the innate and adaptive immune systems are functionally interconnected by pentraxin 3, a soluble pattern recognition receptor that couples innate immune recognition with antibody-inducing function.

Sexual Dimorphism in Innate Immunity

Sexual dimorphisms account for differences in clinical manifestations or incidence of infectious or autoimmune diseases and malignancy between females and males. Females develop enhanced innate and adaptive immune responses than males and are less susceptible to many infections of bacterial, viral, parasitic, and fungal origin and malignancies but in contrast, they are more prone to develop autoimmune diseases. The higher susceptibility to infections in males is observed from birth to adulthood, suggesting that sex chromosomes and not sex hormones have a major role in sexual dimorphism in innate immunity. Sex-based regulation of immune responses ultimately contributes to age-related disease development and life expectancy. Differences between males and females have been described in the expression of pattern recognition receptors of the innate immune response and in the functional responses of phagocytes and antigen presenting cells. Different factors have been shown to account for the sex-based disparity in immune responses, including genetic factors and hormonal mediators, which contribute independently to dimorphism in the innate immune response. For instance, several genes encoding for innate immune molecules are located on the X chromosome. In addition, estrogen and/or testosterone have been reported to modulate the differentiation, maturation, lifespan, and effector functions of innate immune cells, including neutrophils, macrophages, natural killer cells, and dendritic cells. In this review, we will focus on differences between males and females in innate immunity, which represents the first line of defense against pathogens and plays a fundamental role in the activation, regulation, and orientation of the adaptive immune response.

The long pentraxin PTX3: A prototypical sensor of tissue injury and a regulator of homeostasis

Tissue damage frequently occurs. The immune system senses it and enforces homeostatic responses that lead to regeneration and repair. The synthesis of acute phase molecules is emerging as a crucial event in this program. The prototypic long pentraxin PTX3 orchestrates the recruitment of leukocytes, stabilizes the provisional matrix in order to facilitate leukocyte and stem progenitor cells trafficking, promotes swift and safe clearance of dying cells and of autoantigens, limiting autoimmunity and protecting the vasculature. These non‐redundant actions of PTX3 are necessary for the resolution of inflammation. Recent studies have highlighted the mechanisms by which PTX3 adapts the functions of innate immune cells, orchestrates tissue repair and contributes to select the appropriate acquired immune response in various tissues. Conversely, PTX3 continues to be produced in diseases where the inflammatory response does not resolve. It is therefore a valuable biomarker for more precise and personalized stratification of patients, often independently predicting clinical evolution and outcome. There is strong promise for novel therapies based on understanding the mechanisms with which PTX3 plays its homeostatic role, especially in regulating leukocyte migration and the resolution of inflammatory processes.

IL-1 and IL-1 regulatory pathways in cancer progression and therapy

Inflammation is an important component of the tumor microenvironment. IL‐1 is an inflammatory cytokine which plays a key role in carcinogenesis and tumor progression. IL‐1 is subject to regulation by components of the IL‐1 and IL‐1 receptor (ILR) families. Negative regulators include a decoy receptor (IL‐1R2), receptor antagonists (IL‐1Ra), IL‐1R8, and anti‐inflammatory IL‐37. IL‐1 acts at different levels in tumor initiation and progression, including driving chronic non‐resolving inflammation, tumor angiogenesis, activation of the IL‐17 pathway, induction of myeloid‐derived suppressor cells (MDSC) and macrophage recruitment, invasion and metastasis. Based on initial clinical results, the translation potential of IL‐1 targeting deserves extensive analysis.

Innate immunity, hemostasis and matrix remodeling: PTX3 as a link

Innate immunity is evolutionarily connected with hemostasis. PTX3 is an essential fluid-phase pattern recognition molecule of the innate immune system that acts as a functional ancestor of antibodies. PTX3 by interacting with defense collagens and fibrinogens amplifies effector functions of the innate immune system. At wound sites, PTX3 regulates the injury-induced thrombotic response and promotes wound healing by favoring timely fibrinolysis. Therefore, PTX3 interacts with ancestral domains conserved in innate immunity, hemostasis and extracellular matrix and exerts functions related to both antimicrobial resistance and tissue repair. These findings strengthen the connection between innate immune system and hemostasis, and suggest that recognition of microbes and extracellular matrix are evolutionarily conserved and integrated functions of the innate immune system.

Pentraxin-3 is upregulated in the central nervous system during MS and EAE, but does not modulate experimental neurological disease

Pentraxin‐3 (PTX3), an acute‐phase protein released during inflammation, aids phagocytic clearance of pathogens and apoptotic cells, and plays diverse immunoregulatory roles in tissue injury. In neuroinflammatory diseases, like MS, resident microglia could become activated by endogenous agonists for Toll like receptors (TLRs). Previously we showed a strong TLR2‐mediated induction of PTX3 in cultured human microglia and macrophages by HspB5, which accumulates in glia during MS. Given the anti‐inflammatory effects of HspB5, we examined the contribution of PTX3 to these effects in MS and its animal model EAE. Our data indicate that TLR engagement effectively induces PTX3 expression in human microglia, and that such expression is readily detectable in MS lesions. Enhanced PTX3 expression is prominently expressed in microglia in preactive MS lesions, and in microglia/macrophages engaged in myelin phagocytosis in actively demyelinating lesions. Yet, we did not detect PTX3 in cerebrospinal fluid of MS patients. PTX3 expression is also elevated in spinal cords during chronic relapsing EAE in Biozzi ABH mice, but the EAE severity and time course in PTX3‐deficient mice did not differ from WT mice. Moreover, systemic PTX3 administration did not alter the disease onset or severity. Our findings reveal local functions of PTX3 during neuroinflammation in facilitating myelin phagocytosis, but do not point to a role for PTX3 in controlling the development of autoimmune neuroinflammation.

Tuning inflammation and immunity by the negative regulators IL-1R2 and IL-1R8.

Interleukin‐1 receptor family members (ILRs) and Toll‐Like Receptors (TLRs) are key players in immunity and inflammation and are tightly regulated at different levels. Most cell types, including cells of the innate and adaptive immune system express ILRs and TLRs. In addition, IL‐1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cells. IL‐1R2 and IL‐1R8 (also known as TIR8 or SIGIRR) are members of the ILR family acting as negative regulators of the IL‐1 system. IL‐1R2 binds IL‐1 and the accessory protein IL‐1RAcP without activating signaling and can be released as a soluble form (sIL‐1R2), thus modulating IL‐1 availability for the signaling receptor. IL‐1R8 dampens ILR‐ and TLR‐mediated cell activation and it is a component of the receptor recognizing human IL‐37. Here, we summarize our current understanding of the structure and function of IL‐1R2 and IL‐1R8, focusing on their role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer‐related inflammation. We also address the emerging evidence regarding the role of IL‐1R8 as a crucial checkpoint molecule in NK cells in anti‐cancer and antiviral activity and the potential therapeutic implications of IL‐1R8 blockade in specific pathological contexts.

The yin-yang of the interaction between myelomonocytic cells and NK cells

NK cells are innate lymphoid cells, which play a key role in the immune response to cancer and pathogens and participate in the shaping of adaptive immunity. NK cells engage in a complex bidirectional interaction with myelomonocytic cells. In particular, macrophages, dendritic cells and neutrophils promote differentiation and effector function of NK cells and, on the other hand, myelomonocytic cells express triggers of checkpoint blockade (eg PD‐L1) and other immunosuppressive molecules, which negatively regulate NK cell function. In addition, NK cells express high levels of IL‐1R8, which acts as a checkpoint for IL‐18 driven differentiation and activation of NK cells. Evidence suggests that targeting the myeloid cell‐NK cell crosstalk unleashes effective anti‐tumour and anti‐viral resistance.