CANCER RESEARCH | TUMOR BIOLOGY AND IMMUNOLOGY Breast Cancer Cell–Derived Soluble CD44 Promotes Tumor Progression by Triggering Macrophage IL1b Production Jeong-Hoon Jang 1 , Do-Hee Kim 2,3 , Jae Min Lim 4,5 , Joon Won Lee 4,5 , Su Jin Jeong 6 , Kwang Pyo Kim 4,5 , and Young-Joon Surh 1,2,3 ABSTRACT ◥ IL1b is a central regulator of systemic inflammatory response in breast cancer, but the precise regulatory mechanisms that dictate the overproduction of IL1b are largely unsolved. Here, we show that IL1b secretion is increased by the coculture of human monocyte–like cells and triple-negative breast cancer (TNBC) cells. In addition, macrophages robustly produced IL1b when exposed to the conditioned media of TNBC cells. Consistent with these observations, macrophage depletion decreased serum IL1b and reduced breast cancer progression in an orthotopic breast cancer mouse model. Profiling the secretome of human breast cancer cells revealed that the CD44 antigen was the most differentially released protein in basal conditions of TNBC cells. Antibody-mediated neutralization of CD44 abrogated IL1b pro- duction in macrophages and inhibited the growth of primary tumors. These results suggest IL1b-mediated oncogenic signaling is triggered by breast cancer cell membrane–derived soluble CD44 (sCD44) antigen, and targeting sCD44 antigen may pro- vide an alternative therapeutic strategy for breast cancer treat- ment by modulating inflammatory tumor microenvironment. Significance: A novel positive feedback loop between IL1b and CD44 promotes TNBC malignant progression. Introduction Tumor microenvironment is considered to exert a decisive effect on tumor progression (1). In addition to the cancer cells at a primary tumor site, there are various subsets of resident and infiltrated inflam- matory cells including innate and adaptive immune cells, myeloid cells, and lymphoid cells in the tumor microenvironment (2, 3). These cells interplay with one another through complex and dynamic network of chemokines, cytokines, and growth factors (4–6). Tumor-associated inflammatory signaling and their microenviron- mental crosstalk play pivotal roles in different stages of tumor development (7–10). Inflammasomes are multiprotein complexes that promote inflammation through secretion of IL1b in response to microbial infection and endogenous damage-associated molecular patterns (DAMP), such as uric acid, ATP, high mobility group box 1, and the HSP70 and HSP90 (11). IL1b, one of the proinflammatory cytokines, engages innate immune responses through infiltration of inflammatory cells (e.g., neutrophils, macrophages, and mono- cytes) into infection sites (11). Because of its essential roles in innate immune responses, inflammasomes are indispensable for host defense against external infections and tissue damages. In addition to the inflammatory conditions, elevated levels of IL1b have been reported in various types of patients with cancer (7, 12). In breast cancer, it has been demonstrated that aberrant expres- sion of IL1b and inflammasomes is closely associated with progressive and metastatic potential of breast cancer, resulting in poor prognosis (13–16). Nonetheless, the mechanism by which IL1b is released in breast tumor microenvironment remains elusive. The connection between inflammation and cancer can be cate- gorized into two pathways. One is inflammation-induced carcino- genesis, also known as the extrinsic pathway, and the other is cancer-associated inflammation or the intrinsic pathway (17, 18). Many human malignancies are related to inflammation-induced carcinogenesis. Examples are colitis-induced colorectal cancer (19), hepatitis B/C virus–mediated liver cancer (20), Helicobacter pylori– induced gastric cancer (21), liver fluke–associated cholangiocarci- noma (22, 23), and asbestos-associated mesothelioma (24). Com- pared with inflammation-induced carcinogenesis, the mechanism underlying cancer-associated inflammation in breast tumor micro- environment is not fully elucidated. Here we report a novel mechanism responsible for IL1b production in the breast tumor microenvironment. Notably, triple-negative breast cancer (TNBC) cell–derived soluble CD44 (sCD44) antigen promotes IL1b secretion from macrophages. This finding suggests an impor- tance of intercellular communication in tumor microenvironment between breast cancer cells and macrophages via sCD44 antigen–IL1b signaling axis as a novel immunotherapeutic target for better clinical outcomes of patients with TNBC. 1 Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea. 2 Department of Molecular Med- icine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea. 3 Cancer Research Institute, Seoul National University, Seoul, South Korea. 4 Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharma- ceutical Ingredient Materials, Kyung Hee University, Youngin, South Korea. 5 Department of Biomedical Science and Technology, Kyung Hee Medical Sci- ence Research Institute, Kyung Hee University, Seoul, South Korea. 6 Statistics Support Department, Medical Science Research Institute, Kyung Hee University Hospital, Seoul, South Korea. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Corresponding Author: Young-Joon Surh, Seoul National University, 1 Gwanak- ro, Gwank-gu, Seoul 08826, Republic of Korea (South). Phone: 822-880-7845; Fax: 822-883-2906; E-mail: surh@snu.ac.kr Cancer Res 2020;80:1342–56 doi: 10.1158/0008-5472.CAN-19-2288 Ó2020 American Association for Cancer Research. AACRJournals.org | 1342 Downloaded from http://aacrjournals.org/cancerres/article-pdf/80/6/1342/2803202/1342.pdf by KMLA - Kyung Hee University user on 20 December 2022