Antonio Sica

Glutathione Protects Mice from Lethal Sepsis by Limiting Inflammation and Potentiating Host Defense

Neutrophils have a dual role in sepsis-defending against infection and mediating organ failure. Because glutathione (GSH) is lower in sepsis, the hypothesis that GSH depletion might impair the migratory response of neutrophils to infection was tested. In a mouse model of polymicrobial sepsis induced by cecal ligation and puncture, GSH depletion inhibited peritoneal neutrophil infiltration, increased bacterial colonies, augmented pulmonary neutrophil infiltrate, and worsened survival. The reduced peritoneal influx of neutrophils was explained by a reduced in vivo neutrophil migration in response to locally administered chemokines and by reduced chemotactic activity and chemokine levels in peritoneal lavage fluid. Conversely, the GSH precursor N-acetyl-l-cysteine augmented neutrophil infiltration in the peritoneum but not in the lung, decreased bacterial colonies, and improved survival. Thus, migration of neutrophils to a site of infection and to a distant site is differently regulated, and optimal GSH levels are important for an efficient response to sepsis.

Tumor-Associated Macrophages in Cancer Growth and Progression

Tumor development and progression are strongly linked to inflammation and macrophage infiltration is a major component of the inflammatory reactions associated with neoplasia. Plasticity is a hallmark of mononuclear phagocytes, which undergo polarized diverse forms of activation. Metabolic adaptation is a key component of macrophage plasticity and polarization, instrumental to their function in homeostasis, immunity and inflammation. Tumor-associated macrophages (TAM) and related immature myeloid suppressor cells generally have properties of an M2-like population. TAM produce growth factors, have immunoregulatory and immunosuppressive activity, stimulate angiogenesis and provide tissue remodeling, invasion and metastasis. Thus, TAM are a key component of cancer-promoting inflammatory reactions.

The Yin Yang of Cancer Related Inflammation

Smoldering, nonresolving inflammation is part of the tumor microenvironment (Balkwill and Mantovani 2001; Coussens and Werb 2002; Mantovani et al. 2008a). Inflammatory cells and mediators are present in the microenvironment of cancers epidemiologically related or unrelated to inflammatory or infectious conditions. Leukocyte infiltration and the presence of soluble mediators such as cytokines, and chemokines are key characteristics of CRI. Conditions predisposing to cancer (e.g., inflammatory bowel disease, IBD) or genetic events that cause neoplastic transformation orchestrate the construction of an inflammatory microenvironment. Indeed, alterations of oncogenes drive the production of inflammatory mediators. Thus, an intrinsic pathway of inflammation (driven in tumor cells), as well as an extrinsic pathway driven by chronic inflammatory conditions have been identified, both of which contribute to tumor progression (Mantovani et al.

Chapter 16 – Tumor-Associated Macrophages in Cancer Growth and Progression

Publisher Summary This chapter reviews the key properties of tumor-associated macrophages (TAMs), emphasizing on the genetic evidence and the emerging targets for therapeutic intervention. TAMs derive from the circulating monocytes and are recruited at the tumor site by a tumor-derived chemotactic factor for monocytes. TAMs that have immunoregulatory and immunosuppressive activity produce growth factors that stimulate angiogenesis, remodel tissues, and facilitate invasion and metastasis. TAMs and the related immature myeloid suppressor cells have the properties of M2 macrophage populations that are supportive to tumors. In many human tumors, a high frequency of infiltrating TAMs is associated with poor prognosis. TAMs participate in the proangiogenic process by producing the angiogenic factor thymidine phosphorylase (TP), which promotes the endothelial cell migration in vitro and whose levels of expression are associated with tumor neovascularization. TAMs contribute to tumor progression also by producing proangiogenic and tumor-inducing chemokines, such as CCL2. Moreover, TAMs accumulate in the hypoxic regions of tumors, and hypoxia triggers a proangiogenic program in these cells.

Modulation of Innate Immunity by Hypoxia

Low oxygen tension occurs virtually in every site of inflammation, necrotic foci, infection, and wounding. It has become widely recognized that the dynamic interaction between multiple cellular components of damaged tissues, including but not limited to immune and stromal inflammatory cells, and microenvironmental factors, for example, hypoxia, plays a critical role in the pathophysiology of human diseases ranging from infections to chronic inflammation to cancer. Hypoxia modulates leukocyte functions, including migration and survival, by reprogramming the immune responses in pathologic tissues and promoting the innate immune functions of neutrophils, macrophages, and dendritic cells to the disadvantage of adaptive immunity. Strikingly, hypoxia and inflammatory signals share selected transcriptional events, including the activation of members of both the hypoxia-inducible factor and nuclear factor κB families, which may converge to activate specific cell programs. Here, we review the mechanisms of innate immunity adaptation to hypoxia, their role in disease, as well as new perspectives for their therapeutic targeting.

Functions of Diverse Myeloid Cells in the Tumor Micro-Environment

Myeloid cells are abundant in solid tumors and early infiltrate neoplastic lesions since the first stages of tumourigenesis, usually preceding other leukocytes (e.g. lymphocytes). (Clark et al., 2007) In the last decades there has been growing evidence that infiltrating T lymphocytes (CD3+ CD8+CD45RO+) are associated with favourable prognosis in human colorectal cancer (Laghi et al., 2009; Pages et al., 2005) melanoma, ovarian and breast cancer (Clemente et al., 1996; Mahmoud et al., 2011; Vesely et al., 2011; Zhang et al., 2003) In marked contrast, cells of the innate immunity, like myeloid cells, are most frequently associated with poor clinical outcomes. A number of studies have demonstrated that tumorassociated myeloid cells (TAMCs) have the ability to support tumor cell proliferation and invasion, activate the neo-angiogenic switch, and suppress anti-tumor immune responses. (DeNardo et al., 2009; Mantovani et al., 2004a; Martinez et al., 2009; Pollard, 2004; Qian and Pollard, 2010; Talmadge et al., 2007) Thus, in a simplified scheme, adaptive immunity is usually protective and limit tumour progression, while innate immunity favours disease development. However, research in recent years have added a further level of complexity, as components of the adaptive immunity (e.g. IL-4-producing CD4 T cells and antibodyproducing B cells) have been shown to activate innate immune cells in a pro-tumour manner. (DeNardo et al., 2009; Wang and Joyce, 2010) Therefore, the dynamic interplay between tumor-infiltrating cells of the innate and adaptive immunity is of paramount importance for the outcome of tumour progression or regression.

NF-KappaB-Mediated Regulation of Tumour-Associated Macrophages: Mechanisms and Significance

Smoldering inflammation is a component of the tumor microenvironment and represents the seventh hallmark of cancer. Tumor-associated macrophages (TAM) have served as a paradigm for cancer-promoting inflammation. TAM orchestrate various aspects of cancer, including: diversion and skewing of adaptive responses, cell growth; angiogenesis, matrix deposition and remodeling, the construction of a metastatic niche and actual metastasis, and response to hormones and chemotherapeutic agents. Recent studies on human and murine tumors indicate that TAM show a remarkable degree of plasticity and functional heterogeneity, during tumor development. Evidence is accumulating for a “switch” in macrophage phenotypes during the course of tumor progression. Whereas the functions of classically activated, “M1” macrophages during chronic inflammation appear to predispose a given tissue to tumor initiation, in established tumors macrophages exhibit mainly the alternatively activated, “M2” phenotype and resemble “tolerant” macrophages and are engaged in immunosuppression and the promotion of tumor angiogenesis and metastasis.