journal contribution
posted on 2023-03-31, 01:24 authored by Yukino Chiba, Izuru Mizoguchi, Junichi Furusawa, Hideaki Hasegawa, Mio Ohashi, Mingli Xu, Toshiyuki Owaki, Takayuki Yoshimoto This file contains Supplemental Table 1, Supplementary Figure Legends, and Supplementary Figures. Supplemental Table 1 shows primers used in this study. Supplementary Figure Legends describe the legend for each supplementary figure. Figure S1 shows the gating strategy in flow cytometry analysis. Figure S2 shows that IL-27 augments the infiltration of CD11b+ myeloid cells into MC38 tumor. Figure S3 shows that IL-27 promotes the differentiation into M1 macrophages in MC38 tumor-bearing mice. Figure S4 shows that IL-27 much less but significantly augments the infiltration of M1 macrophages into B16F10 tumor when the tumor size in B16F10-IL-27 tumor-bearing mice reaches the similar tumor size to that in control tumor-bearing mice. Figure S5 shows that IL-27 inhibits the differentiation into immunosuppressive macrophages in MC38 tumor-bearing mice. Figure S6 shows the therapeutic potential of the CD11b+ myeloid cells purified from tumors of B16F10-IL-27 tumor-bearing mice on pre-existing tumor model. Figure S7 shows that IL-27-induced MC38 tumor-infiltrating myeloid cells exert direct antitumor effects by killing tumor through NO. Figure S8 shows that the enhanced mRNA expression of immune checkpoint molecules and TGF-β1 in CD11b+ myeloid cells in IL-27-expressing tumor-bearing mice.
Funding
Private University Strategic Research Based Support Project
Ministry of Education, Culture, Sports, Science, and Technology, Japan
Princess Takamatsu Cancer Research Fund
Japan Society for the Promotion of Science
History
ARTICLE 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 in vivo. 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. In vivo 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 Lineage−Sca-1+c-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.Significance: 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.Cancer Res; 78(1); 182–94. ©2017 AACR.
