Interleukin-27 Exerts Its Antitumor Effects by Promoting Differentiation of Hematopoietic Stem Cells to M1 Macrophages

Abstract

The interleukin IL27 promotes expansion and differentiation of hematopoietic stem cells into myeloid progenitor cells. Many tumor-infiltrating myeloid cells exert immunosuppressive effects, but we hypothesized that the myeloid cells induced by IL27 would have antitumor activity. In this study, we corroborated this hypothesis as investigated in two distinct mouse transplantable tumor models. Malignant mouse cells engineered to express IL27 exhibited reduced tumor growth Correlated with this effect was a significant increase in the number of tumor-infiltrating CD11b myeloid cells exhibiting a reduced immunosuppressive activity. Notably, these CD11b cells were characterized by an activated M1 macrophage phenotype, on the basis of increased expression of inducible nitric oxide synthase and other M1 biomarkers. depletion of these cells by administering anti-Gr-1 eradicated the antitumor effects of IL27. When admixed with parental tumors, CD11b cells inhibited tumor growth and directly killed the tumor in a nitric oxide-dependent manner. Mechanistically, IL27 expanded LineageSca-1c-Kit cells in bone marrow. Transplant experiments in Ly5.1/5.2 congenic mice revealed that IL27 directly acted on these cells and promoted their differentiation into M1 macrophages, which mobilized into tumors. Overall, our results illustrated how IL27 exerts antitumor activity by enhancing the generation of myeloid progenitor cells that can differentiate into antitumorigenic M1 macrophages. These findings show how the interleukin IL27 exerts potent antitumor activity by enhancing the generation of myeloid progenitor cells that can differentiate into antitumorigenic M1 macrophages..

Association between IL-27 Gene Polymorphisms and Cancer Susceptibility in Asian Population: A Meta-Analysis

“…IL-27 has potent antitumor activity (Hisada et al, 2004;Chiyo et al, 2005). It exerts antitumor activity by promoting the generation of myeloid progenitor cells that can differentiate into M1 macrophages (Chiba et al, 2018). In addition, IL-27 synergizes with IL-12 to potentiate IFN-γ production by activated naive T-cell and natural killer-cell populations (Pflanz et al, 2002).…”

Investigation of Interleukin-27 in the Sera of Nonmelanoma Skin Cancer Patients

“…Studies have shown the tumor restricting effects of this cytokine on pediatric leukemias [8, 9], lymphomas [10], multiple myeloma (MM) [11], neuroblastoma [12], prostate cancer [13], non-small-cell lung cancer (NSCLC) [14], ovarian cancer (SKOV3 cell line) [15], colon cancer [16], esophageal cancer [17], head and neck squamous cell carcinoma (SCC) [18], and melanoma [19]. These studies have suggested direct inhibition of cell growth/proliferation, migration, tumor angiogenesis, and IL-17 production, alongside with enhancement of NK cell responses, antibody-dependent cell-mediated cytotoxicity (ADCC), generation of myeloid progenitor cells, promoting M1 macrophage differentiation, and most importantly activation and promotion of tumor specific cytotoxic T cell responses as means of antitumor mechanisms by IL-27 [5–7, 20].…”

Protective effects against tumors and infection by interleukin-27 through promotion of expansion and differentiation of hematopoietic stem cells into myeloid progenitors

“…1B). 8 The IL-27-transgenic mice show enhanced myelopoiesis with splenomegaly and extramedullary hematopoiesis in the spleen. 6 Consistent with this, IL-27 together with stem cell factor synergistically and vigorously expands mouse BM cells for a long period.…”

“…1B). 8 The myeloid cells express a higher level of inducible nitric oxide synthase and directly kill tumors, mainly in a nitric oxide-dependent manner. In the BM of tumor-bearing mice, IL-27 increases the LSK cell population, which has an enhanced ability to differentiate into antitumorigenic M1 macrophages.…”

“…In the BM of tumor-bearing mice, IL-27 increases the LSK cell population, which has an enhanced ability to differentiate into antitumorigenic M1 macrophages. 8 These M1 macrophages then infiltrate into tumors and eradicate them.…”