Massimo Locati

The chemokine receptor switch paradigm and dendritic cell migration: Its significance in tumor tissues

Localization in tissues and migration to lymphoid organs are essential steps in the immunobiology of dendritic cells (DC). Chemokines play an important role in guiding the traffic of DC. Receptor expression and responsiveness to constitutively made chemokines account for the presence of DC in normal tissues. Inflammatory chemokines and non-chemokine attractants promote recruitment and localization of DC at sites of inflammation and infection. During maturation, DC undergo a profound and orderly rearrangement of their chemokine receptor repertoire. The chemokine receptor switch paradigm provides a conceptual framework for the complex migration of DC in vivo, including their recruitment and positioning in tumor tissues.

Induction of Functional IL-8 Receptors by IL-4 and IL-13 in Human Monocytes

IL-8 and related Glu-Leu-Arg (ELR+) CXC chemokines are potent chemoattractants for neutrophils but not for monocytes. IL-13 and IL-4 strongly increased CXCR1 and CXCR2 chemokine receptor expression in human monocytes, macrophages, and dendritic cells. The effect was receptor- and cell type-selective, in that CCRs were not increased and no augmentation was seen in neutrophils. The effect was rapid, starting at 4 h, and concentration dependent (EC50 = 6.2 and 8.3 ng/ml for CXCR1 and CXCR2, respectively) and caused by new transcriptional activity. IL-13/IL-4-treated monocytes showed increased CXCR1 and CXCR2 membrane expression. IL-8 and related ELR+ chemokines were potent and effective chemotactic agents for IL-13/IL-4-treated monocytes, but not for untreated mononuclear phagocytes, with activity comparable to that of reference monocyte attractants, such as MCP-1. In the same cells, IL-8 also caused superoxide release. Macrophages and dendritic cells present in biopsies from Omenn’s syndrome and atopic dermatitis patients, two Th2 skewed pathologies, expressed IL-8 receptors by immunohistochemistry. These results show that IL-13 and IL-4 convert IL-8 and related ELR+ chemokines, prototypic neutrophil attractants, into monocyte chemotactic agonists, by up-regulating receptor expression. Therefore, IL-8 and related chemokines may contribute to the accumulation and positioning of mononuclear phagocytes in Th2-dominated responses.

Cell Lineage Commitment and Tumor Microenvironment as Determinants for Tumor-Associated Myelomonocytic Cells Plasticity

Myelomonocytic cells have long been recognized as key elements in tumor biology, with the potential to both elicit tumor and tissue destructive reactions and to promote tumor progression. Tumor-associated macrophages (TAM) from established tumors resemble alternative-activated macrophages associated with the resolution phase of inflammatory reactions and support tumor growth, angiogenesis, tissue remodeling, metastatization, and local immunosuppression. On the other hand, myeloid-derived suppressor cells are released from bone marrow pools in tumor-bearing animals and operate immunosuppressive activities in tumor-draining lymphoid organs, thus contributing to tumor escape from immune surveillance. The ambivalent role of myelomonocytic cells in tumor biology reflects their extraordinary plasticity. Tumor-derived signals in the local microenvironment have long been recognized for their ability to dictate macrophage-polarized activation. More recently, different monocyte subsets have been identified in both human and mouse, and cell lineage commitment is now emerging as a second element dictating cell functional polarization. We will here review current knowledge on the relative contribution of these two elements in the plasticity of myelomonocytic cells in the tumor setting.

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.