Crosstalk between IL-15Rα^(+)tumor-associated macrophages and breast cancer cells reduces CD8+T cell recruitment

作     者：Wenlong Zhang Qing Zhang Nanfei Yang Qian Shi Huifang Su Tingsheng Lin Zhonglei He Wenxin Wang Hongqian Guo Pingping Shen 

作者机构：State Key Laboratory of Pharmaceutical Biotechnology and Department of UrologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolSchool of Life SciencesNanjing UniversityNanjingJiangsu 210023P.R.China Department of UrologyDrum Tower HospitalMedical School of Nanjing UniversityInstitute of UrologyNanjing UniversityNanjingJiangsu 210008P.R.China Shenzhen Research Institute of Nanjing UniversityShenzhen 518000China Department of Cellular and Integrative PhysiologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas 78229-3904USA Charles Institute of DermatologySchool of MedicineUniversity College DublinDublin Eircode D04 V1W8Ireland 

出 版 物：《Cancer Communications》 (癌症通讯（英文）)

年 卷 期：2022年第42卷第6期

页      面：536-557页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：National Key Research and Development Plan,Grant/Award Number:2017YFA0506000 Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2021B1515120016 National Natural Science Foundation of China,Grant/Award Number:82072822 the Key Research and Development Program of Jiangsu Province,China-Social Development Projects,Grant/Award Number:BE2020687。 

主　　题：breast cancer CD8^(+)T-cell crosstalk IL-15Rα immunotherapy tumor microenvironment tumor-associated macrophages 

摘      要：Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance.Herein,this study aimed to obtain in-depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression.Methods:T-cell killing assays and co-culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL-15.Western blotting,histological analysis,CRISPR-Cas9 knockout,multi-parameter flow cytometry,and tumor cell-macrophage co-injection mouse models were developed to examine the mechanism by which IL-15Rα^(+)tumor-associated macrophages(TAMs)regulate breast cancer cell resistance to IL-15.Results:We found thatmacrophages contributed to the resistance of tumor cells to IL-15,and tumor cells induced macrophages to express high levels of theαsubunit of the IL-15 receptor(IL-15Rα).Further investigation showed that IL-15Rα^(+)TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1(CX3CL1)in tumor cells to inhibit the recruitment of CD8^(+)T cells by releasing the IL-15/IL-15Rαcomplex(IL-15Rc).Administration of an IL-15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti-programmed cell death protein 1(PD-1)antibody immunotherapy.Interestingly,Granulocyte-macrophage colony-stimulating factor(GMCSF)inducedγchain(γc)expression to promote tumor cell-macrophage crosstalk,which facilitated tumor resistance to IL-15.Additionally,we observed that the non-transcriptional regulatory function of hypoxia inducible factor-1alpha(HIF-1α)was essential for IL-15Rc to regulateCX3CL1 expression in tumor cells.Conclusions:The IL-15Rc-HIF-1α-CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumormicroenvironment of breast cancer.Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.