Search

Tumor-associated myeloid cells (TAMCs), mainly represented by tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), can promote tumor growth directly, by favouring tumor cell proliferation and survival, and indirectly, by creating an immunosuppressive microenvironment. Myeloid cells are characterized by an extreme phenotypical and functional plasticity. Immunometabolism is now emerging as a crucial aspect of TAMCs skewing towards pro-tumoral activities. The metabolic re-education of myeloid cells is a new strategy to boost their anti-tumor effector functions. Several anticancer therapies targeting TAMCs are already under investigation. Nowadays, the hot topic of cancer immunotherapy is represented by immune checkpoint inhibitors. These drugs unrestrain T cell-mediated tumor elimination by removing suppressive signals delivered by tumor-associated cells. The efficacy of immune checkpoint blockade can be enhanced using coordinated strategies to counteract the TAMCs-dependent impairment of immune adaptive responses. In the first part of the review, we will describe the association between metabolic reprogramming and TAMCs biological activities. In the second part, we will illustrate the potential of combination therapies associating TAMC-targeting drugs with immune checkpoint inhibitors. This article is protected by copyright. All rights reserved.

Mononuclear phagocyte plasticity includes the expression of functions related to the resolution of inflammation, tissue repair and remodelling, particularly when these cells are set in an M2 or an M2-like activation mode. Macrophages are credited with an essential role in remodelling during ontogenesis. In extraembryonic life, under homeostatic conditions, the macrophage trophic and remodelling functions are recapitulated in tissues such as bone, mammary gland, decidua and placenta. In pathology, macrophages are key components of tissue repair and remodelling that occur during wound healing, allergy, parasite infection and cancer. Interaction with cells bearing stem or progenitor cell properties is likely an important component of the role of macrophages in repair and remodelling. These properties of cells of the monocyte-macrophage lineage may represent a tool and a target for therapeutic exploitation.

An intrinsic (oncogene-driven) pathway and an extrinsic (microenvironment-driven) pathway connect inflammatory reactions and cancer. M2-polarized tumor-associated macrophages and the related myeloid-derived suppressor cells are key prototypic components of smoldering inflammation driving neoplastic progression. However, mononuclear phagocytes can exert anti-tumor activity by killing tumor cells and eliciting tissue disruptive reactions (M1), a likely scenario in the early phases of carcinogenesis of immunogenic tumors and following therapeutic intervention. Shifting the macrophage balance represents a viable therapeutic target. Herein, the 'macrophage balance' is discussed in the context of the apparent paradox of tumor promotion by innate immunity-driven inflammation and the seemingly opposed tumor surveillance by adaptive immune responses.

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.

Plasticity and heterogeneity are hallmarks of myelomonocytic differentiation and polarized activation. Evidence published in this issue of the European Journal of Immunology, together with other recent data, add new elements and perspectives to the current understanding of mononuclear phagocyte differentiation and activation and are discussed in this Commentary.

Convergent pathways of macrophage polarization: The role of B cells Antonio Sica, Chiara Porta, Elena Riboldi and Massimo Locati In the above manuscript, the affiliations for Massimo Locati were incorrectly given as DISCAFF, University of Piemonte Orientale A. Avogadro, Novara, Italy; and Department of Translational Medicine, University of Milan, I-20089, Rozzano, Milan, Italy. The correct affiliations are Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Clinico Humanitas, Rozzano, Italy; and Department of Translational Medicine, University of Milan, Rozzano, Milan, Italy. Correction