title: Intratumoral Delivery of IL-21 Overcomes Anti-Her2/Neu Resistance through Shifting Tumor-Associated Macrophages from M2 to M1 Phenotype.
abstract: Tumor resistance is a major hurdle to anti-Her2/neu Ab-based cancer therapy. Current strategies to overcome tumor resistance focus on tumor cell-intrinsic resistance. However, the extrinsic mechanisms, especially the tumor microenvironment, also play important roles in modulating the therapeutic response and resistance of the Ab. In this study, we demonstrate that tumor progression is highly associated with TAMs with immune-suppressive M2 phenotypes, and deletion of TAMs markedly enhanced the therapeutic effects of anti-Her2/neu Ab in a HER2/neu-dependent breast cancer cell TUBO model. Tumor local delivery of IL-21 can skew TAM polarization away from the M2 phenotype to a tumor-inhibiting M1 phenotype, which rapidly stimulates T cell responses against tumor and dramatically promotes the therapeutic effect of anti-Her2 Ab. Skewing of TAM polarization by IL-21 relies substantially on direct action of IL-21 on TAMs rather than stimulation of T and NK cells. Thus, our findings identify the abundant TAMs as a major extrinsic barrier for anti-Her2/neu Ab therapy and present a novel approach to combat this extrinsic resistance by tumor local delivery of IL-21 to skew TAM polarization. This study offers a therapeutic strategy to modulate the tumor microenvironment to overcome tumor-extrinsic resistance.
authors: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China; and.
authors: Meng
authors: M
authors: Xu
authors: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China; and.
authors: Mingyue
authors: M
authors: Liu
authors: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China; and.
authors: Xuexiang
authors: X
authors: Du
authors: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China; and.
authors: Sirui
authors: S
authors: Li
authors: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors: Hang
authors: H
authors: Li
authors: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors: Xiaozhu
authors: X
authors: Li
authors: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors: Ying
authors: Y
authors: Li
authors: Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL 60637.
authors: Yang
authors: Y
authors: Wang
authors: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors: Zhihai
authors: Z
authors: Qin
authors: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL 60637 sdwang@moon.ibp.ac.cn yfu@uchicago.edu.
authors: Yang-Xin
authors: YX
authors: Fu
authors: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; sdwang@moon.ibp.ac.cn yfu@uchicago.edu.
authors: Shengdian
authors: S
authors: Wang
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007378:Interleukins / Q000008:administration & dosage / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D000068878:Trastuzumab; D059016:Tumor Microenvironment / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007378:Interleukins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D000098546:Interleukin-21