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Chemotherapy-Induced IL34 Enhances Immunosuppression By Published OnlineFirst August 22, 2016; DOI: 10.1158/0008-5472.CAN-16-1170 Cancer Microenvironment and Immunology Research Chemotherapy-Induced IL34 Enhances Immunosuppression by Tumor-Associated Macrophages and Mediates Survival of Chemoresistant Lung Cancer Cells Muhammad Baghdadi1, Haruka Wada1, Sayaka Nakanishi1, Hirotake Abe1, Nanumi Han1, Wira Eka Putra1, Daisuke Endo2, Hidemichi Watari2, Noriaki Sakuragi2, Yasuhiro Hida3, Kichizo Kaga3, Yohei Miyagi4, Tomoyuki Yokose5, Atsushi Takano6,7, Yataro Daigo6,7, and Ken-ichiro Seino1 Abstract The ability of tumor cells to escape immune destruction and enhance local immunosuppression and to promote the sur- their acquired resistance to chemotherapy are major obstacles vival of chemoresistant cancer cells by activating AKT signal- to effective cancer therapy. Although immune checkpoint ther- ing. Targeting IL34 in chemoresistant tumors resulted in a apiessuchasanti-PD-1addresstheseissuesinpart,clinical remarkable inhibition of tumor growth when accompanied responses remain limited to a subpopulation of patients. In this with chemotherapy. Our results define a pathogenic role for report, we identified IL34 produced by cancer cells as a driver IL34 in mediating immunosuppression and chemoresistance of chemoresistance. In particular, we found that IL34 modu- and identify it as a tractable target for anticancer therapy. lated the functions of tumor-associated macrophages to Cancer Res; 76(20); 1–13. Ó2016 AACR. Introduction In addition, recent advances in cancer immunology have sug- gested that the therapeutic resistance of tumors also relies impor- Although recent progress in cancer research has helped to tantly on extrinsic mechanisms represented by the cross-talk develop new selective treatments based on increased understand- between tumor cells and other cellular components of the tumor ing of cancer biology, chemotherapy is still one of the most microenvironment (TME), in particular immune cells (4). Indeed, common treatment options for many cancers (1). Chemotherapy understanding the complex interaction between cancer and is used to induce cell death in tumors and augment immune immune system has provided unique therapeutic opportunities responses to cancer. However, many cancer patients experience to improve the clinical benefit of chemotherapy; for example, recurrence and ultimately death because of chemoresistance and combining chemotherapy with antibodies that target immune- chemotherapy-induced immunosuppression. In the past few checkpoint molecules such as programmed cell death-1 (PD-1) in decades, several studies have underlined intrinsic mechanisms advanced non–small lung cancer patients (5). In spite of its that occur inside cancer cells and contribute to chemoresistance promising results, clinical responses are still limited to a subpop- such as the induction of antiapoptotic regulators, ABC transpor- ulation of patients (6), and identifying new therapeutic targets is ters, aberrant NF-kB activities, and DNA damage machinery (2, 3). critically needed. Tumor-associated macrophages (TAM) constitute the domi- nant myeloid cell population in many tumors and play critical 1Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. 2Department of Obstetrics and Gynecol- roles in multiple aspects of TME, including therapeutic resistance ogy, Graduate School of Medicine, Hokkaido University, Sapporo, (7–9). Importantly, increased frequency of protumorigenic TAMs Japan. 3Department of Cardiovascular and Thoracic Surgery, following chemotherapy is a hallmark of developing chemore- Graduate School of Medicine, Hokkaido University, Sapporo, Japan. sistance and correlate with poor clinical outcomes (7–9). In 4Molecular Pathology and Genetics Division, Kanagawa Cancer Cen- ter, Yokohama, Japan. 5Department of Pathology, Kanagawa Cancer particular, M2-polarized TAMs drive multiple protumorigenic Center, Yokohama, Japan. 6Department of Medical Oncology and processes, including immunosuppression, angiogenesis, metas- Cancer Center, Shiga University of Medical Science, Otsu, Japan. tasis, tumor survival, and cancer cell stemness (7–12). Consistent 7Center for Antibody and Vaccine, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan. with this, targeting of macrophages by colony stimulating factor 1 receptor (CSF1R) inhibitors or blocking mAbs showed promising Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). effects to improve chemotherapeutic responses (13, 14). How- ever, considering the critical roles of macrophages in homeostasis M. Baghdadi and H. Wada contributed equally to this article. and innate immunity, there are concerns about side effects that Corresponding Author: Ken-ichiro Seino, Institute for Genetic Medicine, Hok- may arise from extended depletion of these cells at the systemic kaido University, Kita-15, Nishi-7, Sapporo 060-0815, Japan. Phone: 81-11-706- level. Alternatively, targeting factors induced by chemotherapy 5532; Fax: 81-11-706-7545; E-mail: [email protected] and affecting macrophage polarization may have the potential to doi: 10.1158/0008-5472.CAN-16-1170 improve the clinical outcome of cytotoxic chemotherapy with Ó2016 American Association for Cancer Research. fewer side effects. Accordingly, further investigations are needed www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst August 22, 2016; DOI: 10.1158/0008-5472.CAN-16-1170 Baghdadi et al. to identify mechanisms that drive macrophage polarization under cell lines were obtained from the ATCC. KFr and TuoM-1 cell chemotherapeutic conditions. lines were provided by Prof. Yoshihiro Kikuchi (National To identify such mechanisms, we developed a model of Defense Medical College, Saitama, Japan) and Prof. Junzo Kigawa chemoresistance in lung cancer cells, the major leading cause (Tottori University, School of Medicine), respectively. OVISE and of cancer-related deaths in the world and frequently accompa- OVTOKO cell lines were obtained from JCRB (Japanese Collec- nied with chemoresistance (15). Using this model, we identi- tion of Research Bio resources, Osaka, Japan). All cell lines were fied IL34 as a novel factor that contributes to immunosuppres- cultured at 37 C with 5% CO2 in an appropriate culture medium. sion and survival of chemoresistant cancer cells in chemother- apy-treated TME. In this report, we described the role of IL34 as Generation of chemoresistant cells a molecular driver of chemoresistance, and discuss the signif- Lung cancer cells were exposed to stepwise increasing concen- icance of these basic findings on clinical applications in cancer trations of standard chemotherapies, including doxorubicin patients. (0.01–1 mmol/L) or cisplatin (0.01–0.1 mmol/L). In each cycle, cells were treated with cytotoxic agent for 72 hours, and then drug Materials and Methods was washed and cells were allowed to recover. After reaching Cell culture maximal concentrations, chemoresistant cells were exposed All cell lines were obtained in 2013 as follows. Lung (A549, to maximal toxic concentrations at regular intervals to maintain H1299), breast (MCF7, MDA-MB-231, MDA-MB-436, T47D), their drug resistance. In experiments that use supernatants of liver (Hep3B, HepG2), and colon (HCT116, SW480) cancer cell culture, chemoresistant cells were washed 5 times with Figure 1. Monocytes differentiate into M2-polarized macrophages with enhanced immunosuppressive phenotype when stimulated with supernatants of chemoresistant cells. A, frequencies of CD14þCD11bþ fraction in PBLs treated for 7 days with media or supernatants of chemosensitive (A549-DS) or chemoresistant (A549-DR) cells as evaluated by FACS (left) and graph (right). Forward scatter (FSC) and side scatter (SSC) parameters were used to detect cell size distributionand perform initial gating to remove debris. B, representative photomicrographs of macrophages differentiated from monocytes cultured for 7 days in the presence of A549-DS or A549-DR supernatants. C and D, FACS analysis for CD68 (C) or CD163 (D) expression in purified CD14þ monocytes cultured in media or in the presence of A549-DS or A549-DR supernatants for 7 days. Large cells were gated on the basis of forward scatter and side scatter. Mean fluorescence intensity (MFI) of monocytes was considered as 1. E, qRT-PCR analysis of various cytokines and chemokines expression in A549-DS-MÈ or A549-DR-MÈ. Data from purified CD14þ monocytes were set as 1. F, evaluation of the immunosuppressive function of macrophages. A549-DS-MÈ or A549-DR-MÈ were cocultured with autologous CD4 or CD8 T cells stimulated with anti-CD3/28 for 72 hours (ratio 1:5) and IFNg production was determined by ELISA. Data, as mean Æ SEM; Ã, P < 0.05. OF2 Cancer Res; 76(20) October 15, 2016 Cancer Research Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst August 22, 2016; DOI: 10.1158/0008-5472.CAN-16-1170 An Importance of IL34 in Cancer Chemoresistance sterilized PBS, and cultured in media without doxorubicin. The Humanized mouse model À À supernatants were harvested 72 hours later and passed through NOD-SCID-IL2rg / mice (females, 6 weeks old) were 0.2-mm filter. irradiated as described previously (2.5 G; refs. 16, 17) and transferred after 24 hours with 1 Â 105 human bone marrow Human monocyte culture
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