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Interleukin-27 Exerts Its Antitumor Effects By Published OnlineFirst November 1, 2017; DOI: 10.1158/0008-5472.CAN-17-0960 Cancer Tumor Biology and Immunology Research Interleukin-27 Exerts Its Antitumor Effects by Promoting Differentiation of Hematopoietic Stem Cells to M1 Macrophages Yukino Chiba, Izuru Mizoguchi, Junichi Furusawa, Hideaki Hasegawa, Mio Ohashi, Mingli Xu, Toshiyuki Owaki, and Takayuki Yoshimoto Abstract The interleukin IL27 promotes expansion and differentiation of antitumor effects of IL27. When admixed with parental tumors, þ hematopoietic stem cells into myeloid progenitor cells. Many CD11b cells inhibited tumor growth and directly killed the tumor tumor-infiltrating myeloid cells exert immunosuppressive effects, in a nitric oxide-dependent manner. Mechanistically, IL27 expand- À þ þ but we hypothesized that the myeloid cells induced by IL27 would ed Lineage Sca-1 c-Kit cells in bone marrow. Transplant experi- have antitumor activity. In this study, we corroborated this hypoth- ments in Ly5.1/5.2 congenic mice revealed that IL27 directly acted esis as investigated in two distinct mouse transplantable tumor on these cells and promoted their differentiation into M1 macro- models. Malignant mouse cells engineered to express IL27 exhib- phages, which mobilized into tumors. Overall, our results illus- ited reduced tumor growth in vivo. Correlated with this effect was a trated how IL27 exerts antitumor activity by enhancing the gener- þ significant increase in the number of tumor-infiltrating CD11b ation of myeloid progenitor cells that can differentiate into anti- myeloid cells exhibiting a reduced immunosuppressive activity. tumorigenic M1 macrophages. þ Notably, these CD11b cells were characterized by an activated M1 Significance: These findings show how the interleukin IL27 macrophage phenotype, on the basis of increased expression of exerts potent antitumor activity by enhancing the generation of inducible nitric oxide synthase and other M1 biomarkers. In vivo myeloid progenitor cells that can differentiate into antitumori- depletion of these cells by administering anti–Gr-1 eradicated the genic M1 macrophages. Cancer Res; 78(1); 182–94. Ó2017 AACR. Introduction M2 macrophage phenotype is characterized by immunoregu- latory functions leading to the promotion of tissue remodeling Although immunotherapeutic approaches against cancer are and tumor progression. promising new treatments, their effectiveness can be further IL27 is an IL12 family cytokine that consists of two distinct improved by overcoming the immunosuppression induced by subunits, Epstein-Barr virus-induced gene 3 and p28, and its tumors. These immunosuppressive mechanisms include receptor (R) is composed of IL27Ra (WSX-1/TCCR) and gly- immune checkpoint molecules, regulatory T cells, and immu- coprotein 130 (4, 5). It is one of the pleiotropic cytokines with nosuppressive myeloid cells. Generally, tumor-bearing hosts both pro- and anti-inflammatory properties acting on various and cancer patients have increased infiltration of immunosup- cell types. IL27 promotes the early induction of Th1 differen- pressive myeloid cells, including tumor-associated macro- tiation and generation of cytotoxic lymphocytes, but it inhibits phages, M2 macrophages, and myeloid-derived suppressor the differentiation to Th2 and Th17 cells and suppresses the cells (MDSC; refs. 1, 2). Macrophages are characterized by production of pro-inflammatory cytokines (4, 5). Because we high plasticity and diversity with two major phenotypes, first demonstrated the antitumor efficacy of IL27 in 2004 using namely M1 (classically activated) and M2 (alternatively acti- a transplanted mouse tumor genetically engineered to secrete vated) macrophages (3). The M1 macrophage phenotype is IL27 as a preclinical tumor model (6), accumulating evidence characterized by the production of pro-inflammatory cyto- suggests that IL27 has potent antitumor activity through mul- kines, reactive oxygen species, and nitric oxide (NO) and the tiple mechanisms, depending on the characteristics of individ- promotion of helper T (Th) 1 immune responses, resulting in ual tumors (7, 8). Moreover, we recently demonstrated that strong microbicidal and tumoricidal activity. In contrast, the IL27 can promote the expansion and differentiation of hemato- poietic stem cells (HSC) into myeloid progenitor cells and that Department of Immunoregulation, Institute of Medical Science, Tokyo Medical it plays a critical role in the control of parasite infection during University, Shinjuku-ku, Tokyo, Japan. emergency myelopoiesis (9, 10). Note: Supplementary data for this article are available at Cancer Research IL27wasalsodemonstratedtoaugmenttheproduction Online (http://cancerres.aacrjournals.org/). of immunosuppressive cytokine IL10 and enhance expression Corresponding Author: Takayuki Yoshimoto, Department of Immunoregula- of the immune checkpoint molecules such as programmed tion, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, death-1 ligand 1 (PD-L1) and T-cell immunoglobulin and Shinjuku-ku, Tokyo 160-8402, Japan. Phone: 81-3-3351-6141; Fax: 81-3-3351- mucin domain-3 (TIM-3) in lymphocytes and macrophages 6250; E-mail: [email protected] (11–15). In addition, IL27 was recently shown to upregulate doi: 10.1158/0008-5472.CAN-17-0960 another immunosuppressive molecule, CD39, together with Ó2017 American Association for Cancer Research. PD-L1 and IL10 in macrophages, resulting in acquisition of 182 Cancer Res; 78(1) January 1, 2018 Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst November 1, 2017; DOI: 10.1158/0008-5472.CAN-17-0960 Differentiation to Antitumorigenic M1 Macrophages by IL27 immunoregulatory properties by tumor-associated macro- class II I-A/I-E (M5/114.15.2), Ly6G (1A8), Ly6C (HK1.4), phages in various cancer patients (16, 17). These results indi- CD45.1 (A20), and CD45.2 (104) were purchased from Bio- cate that macrophages may play an inhibitory role in the Legend. mAbs against mouse CD4 (GK1.5), CD34 (RAM34), exertion of antitumor activity by IL27. However, myeloabla- and CD86 (GL1) were purchased from eBioscience. APC-Cy7– tion by treosulfan, a chemotherapy drug used to induce a severe conjugated streptavidin, PerCP/Cy5.5-conjugated streptavidin, or complete depletion of bone marrow (BM) cells including and Brilliant Violet 510-conjugated streptavidin were pur- cells other than macrophages, was recently shown to mostly chased from BioLegend and used to reveal staining with bio- abolish the antitumor effects of IL27 in mice bearing non- tinylated Abs. Mouse recombinant IL27 was prepared as a small cell lung cancer (18). Moreover, IL27 inhibited the tagged single-chain fusion protein by flexibly linking EBI3 to development of M2 macrophages from the human monocytic p28 using HEK293-F cells (Life Technologies), as described cell line U937 differentiated by phorbol 12–myristate 13– previously (22). Mouse recombinant stem cell factor (SCF) acetate and subsequently polarized by IL4 (19). Therefore, our and IL3 were purchased from PeproTech. Depletion mAb to understanding of the role of macrophages in the exertion of Gr-1 (RB6-8C5) was obtained from BioXCell. NG-monomethyl antitumor activity by IL27 remains incomplete. L-arginine (L-NMMA) was purchased from Sigma-Aldrich. Although the mouse transplantable tumor model genetically engineered to secrete IL27 significantly decreased tumor growth Preparation of transfectants (20, 21), we initially noticed that the number of tumor-infil- B16F10 and MC38 tumor cells were transfected with the þ trating cells, including CD11b myeloid cells greatly increased. expression vector of a FLAG-tagged single-chain fusion protein Therefore, we wondered whether these myeloid cells would be of IL27–expression vector in p3xFLAG-CMV-14 vector (Sigma- protumorigenic or antitumorigenic. In the present study, to Aldrich; ref. 6) or empty vector as control using Fugene 6 (Roche) clarify this, we used two distinct mouse transplantable tumor and selected with Geneticin (G418). Resultant respective trans- models, B16F10 melanoma and MC38 colon adenocarcinoma. fectants were designated as B16F10-IL27 or MC38-IL27 and Our results clearly revealed a novel mechanism whereby IL27 B16F10-Vector or MC38-Vector, respectively. exerts antitumor activity by promoting expansion and differ- entiation of HSCs into antitumorigenic M1 macrophages in Transplantable mouse tumor models tumor-bearing mice. Tumor cells (1 Â 106 cells/mouse) of B16F10 or MC38 were injected subcutaneously into the right flank of mice (n ¼ 3–5). Tumor growth was monitored twice a week with an electronic Materials and Methods caliper and expressed as volume (mm3) by calculating using the Cell lines and mice following volume equation: 0.5(ab2), where a is the long diameter Mouse melanoma cell line B16F10 and colon carcinoma cell and b is the short diameter. line MC38 were kindly provided by Dr. Nariuchi (University of Tokyo, Tokyo, Japan) in 2007 and by Dr. Kawakami (Keio Flow cytometry University, Tokyo, Japan) in 2014, respectively. These cell lines On days 13 to 22 after tumor implantation, tumor was har- were expanded in our laboratory, frozen immediately, and vested from mice (n ¼ 3–5), minced into small pieces, and treated stored in liquid nitrogen to ensure that cells used for experi- with collagenase. Subsequently, tumor-infiltrating mononuclear ments were passaged for fewer than 6 months. Early passage cells were purified from it by Percoll (GE Healthcare) density
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