Abstract
In the last few years, a new actor hit the scene of the tumor microenvironment, the p28 subunit of interleukin (IL)-27, known as IL-30. Its molecular structure allows it to function as an autonomous cytokine and, alternatively, to pair with other subunits to form heterodimeric complexes and enables it to play different, and not fully elucidated, roles in immunity. However, data from the experimental models and clinical samples, suggest IL-30′s engagement in the relationship between cancer and myeloid cells, which fosters the tumor microenvironment and the cancer stem cell niche, boosting the disease progression. Activated myeloid cells are the primary cellular source and one of the targets of IL-30, which can also be produced by cancer cells, especially, in aggressive tumors, as observed in the breast and prostate. This review briefly reports on the immunobiology of IL-30 and related cytokines, by comparing mouse and human counterparts, and then focuses on the mechanisms whereby IL-30 amplifies intratumoral myeloid cell infiltrate and triggers a vicious cycle that worsens immunosuppression in the tumor microenvironment (TME) and constitutes a real threat for a successful immunotherapeutic strategy.
Highlights
Tumor-associated immune cells and their crosstalk with cancer and the components of its microenvironment dramatically affect tumor behavior and patient outcome [1,2]
TNFα, IL-1, and multiple Toll-Like Receptor (TLR)s [48]. These findings suggest a context-dependent activation versus suppressive functions of IL-27 in innate immunity and highlight its homeostatic role in limiting macrophage activation through inflammatory cytokines
Such as for the best known and longer studied homologue cytokine IL-6 [78,79], a prominent role is emerging for IL-30 in tumorigenesis, given its ability in shaping the tumor microenvironment (TME) and cancer stem cell niche, in which myeloid cells are critically involved
Summary
Tumor-associated immune cells and their crosstalk with cancer and the components of its microenvironment dramatically affect tumor behavior and patient outcome [1,2]. Cells 2020, 9, 615 of reactive oxygen species (ROS), nitric oxide (NO), and ectoenzymes, which regulate the adenosine metabolism; expression of immune checkpoint molecules [10,11]; depletion of metabolites critical for lymphocyte functions [12,13]; and through their secretion of growth, angio- lymph-angiogenic factors and inflammatory mediators [13], that are crucial for tissue remodeling and tumor development Recent insights into this inflammatory milieu, in breast (BC) and prostate (PC) cancers, have unveiled a role for the novel immunoregulatory mediator Interleukin(IL)-30/IL-27p28 [14] in the TME and in the intricate relationship between cancer and myeloid cells, which orchestrates tumor-promoting events with evident clinical implications [15,16]. Genes encoding for homologs of IL-27 subunits have been identified in nearly 20 mammalian species [17]
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