RRC ID 58371
Author Jing W, Guo X, Wang G, Bi Y, Han L, Zhu Q, Qiu C, Tanaka M, Zhao Y.
Title Breast cancer cells promote CD169+ macrophage-associated immunosuppression through JAK2-mediated PD-L1 upregulation on macrophages.
Journal Int Immunopharmacol
Abstract Macrophages are recognized as one of the major cell types in tumor microenvironment, and macrophage infiltration has been predominantly associated with poor prognosis among patients with breast cancer. Using the murine models of triple-negative breast cancer in CD169-DTR mice, we found that CD169+ macrophages support tumor growth and metastasis. CD169+ macrophage depletion resulted in increased accumulation of CD8+ T cells within tumor, and produced significant expansion of CD8+ T cells in circulation and spleen. In addition, we observed that CD169+ macrophage depletion alleviated tumor-induced splenomegaly in mice, but had no improvement in bone loss and repression of bone marrow erythropoiesis in tumor-bearing mice. Cancer cells and tumor associated macrophages exploit the upregulation of the immunosuppressive protein PD-L1 to subvert T cell-mediated immune surveillance. Within the tumor microenvironment, our understanding of the regulation of PD-L1 protein expression is limited. We showed that there was a 5-fold higher relative expression of PD-L1 on macrophages as compared with 4T1 tumor cells; coculture of macrophages with 4T1 cells augmented PD-L1 levels on macrophages, but did not upregulate the expression of PD-L1 on 4T1 cells. JAK2/STAT3 signaling pathway was activated in macrophages after coculture, and we further identified the JAK2 as a critical regulator of PD-L1 expression in macrophages during coculture with 4T1 cells. Collectively, our data reveal that breast cancer cells and CD169+ macrophages exhibit bidirectional interactions that play a critical role in tumor progression, and inhibition of JAK2 signaling pathway in CD169+ macrophages may be potential strategy to block tumor microenvironment-derived immune escape.
Volume 78
Pages 106012
Published 2020-1-1
DOI 10.1016/j.intimp.2019.106012
PII S1567-5769(19)31583-8
PMID 31865052
MeSH Animals Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use B7-H1 Antigen / immunology B7-H1 Antigen / metabolism* Cell Communication / immunology Cell Culture Techniques Cell Line, Tumor / transplantation Coculture Techniques Diphtheria Toxin / pharmacology Disease Models, Animal Female Humans Janus Kinase 2 / antagonists & inhibitors Janus Kinase 2 / metabolism* Macrophages / drug effects Macrophages / immunology* Macrophages / metabolism Mice Primary Cell Culture Pyrazoles / pharmacology Pyrimidines / pharmacology Sialic Acid Binding Ig-like Lectin 1 / metabolism Signal Transduction / drug effects Signal Transduction / immunology Triple Negative Breast Neoplasms / immunology* Triple Negative Breast Neoplasms / pathology Tumor Escape / drug effects Tumor Escape / immunology* Tumor Microenvironment / immunology* Up-Regulation
IF 3.943
Times Cited 1
Mice RBRC04395