Immunology and Biotherapies

Abstract

Chemokines and chemokine receptors orchestrate cell migration and homing in the body. Humans have at least 44 chemokines that are further classified into four subfamilies based on the N-terminal conserved cysteine motifs: CXC, CC, C and CX3C. All the known chemokine receptors are seven transmembrane-type receptors. Humans have 18 chemotactic and 5 atypical non-chemotactic (recycling or scavenging) receptors. CC chemokine receptor 4 (CCR4) is the receptor for two CC chemokine ligands (CCLs)—CCL17 (also called thymus- and activation-regulated chemokine) and CCL22 (macrophage-derived chemokine). Among the various T-cell subsets, CCR4 is predominantly expressed by Th2 cells, cutaneous lymphocyte antigen-positive skin-homing T cells and Treg cells. Thus, CCR4 attracts much attention for its possible clinical applications in diseases involving these T-cell subsets. Furthermore, CCR4 is often highly expressed by mature T-cell neoplasms such as adult T-cell leukemia/lymphoma (ATL) and cutaneous T-cell lymphomas (CTCLs). This article is a brief overview of basic and clinical research on CCR4 and its ligands, which has eventually led to the development of a humanized defucosylated anti-CCR4 antibody ‘Mogamulizumab’ for treatment of relapsed/refractory ATL and CTCLs.

Via Krishan Maggon

Highlights

 

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Mast cells are found in large numbers at solid tumor sites and can have both pro-tumorigenic and anti-tumorigenic roles.

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Multiple pathways, including hypoxia, adenosine, TLR, antibody and complement, can activate mast cells in solid tumors.

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Activated mast cells recruit immune effector and regulatory cells and mobilize dendritic cell responses.

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Mast cells are excellent targets for cancer immunotherapy due to their location, prolonged lifespan and radio-resistance.

 

Abstract

Mast cells have historically been studied mainly in the context of allergic disease. In recent years, we have come to understand the critical importance of mast cells in tissue remodeling events and their role as sentinel cells in the induction and development of effective immune responses to infection. Studies of the role of mast cells in tumor immunity are more limited. The pro-tumorigenic role of mast cells has been widely reported. However, mast cell infiltration predicts improved prognosis in some cancers, suggesting that their prognostic value may be dependent on other variables. Such factors may include the nature of local mast cell subsets and the various activation stimuli present within the tumor microenvironment. Experimental models have highlighted the importance of mast cells in orchestrating the anti-tumor events that follow immunotherapies that target innate immunity. Mast cells are long-lived tissue resident cells that are abundant around many solid tumors and are radiation resistant making them unique candidates for combined treatment modalities. This review will examine some of the key roles of mast cells in tumor immunity, with a focus on potential immunotherapeutic interventions that harness the sentinel role of mast cells.

Via Krishan Maggon