Intratumoral delivery of IL-21 overcomes anti-Her2/Neu resistance through shifting tumor-associated macrophages from M2 to M1 phenotype

Meng Xu, Mingyue Liu, Xuexiang Du, Sirui Li, Hang Li, Xiaozhu Li, Ying Li, Yang Wang, Zhihai Qin, Yang Xin Fu, Shengdian Wang

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4997-5006
Number of pages10
JournalJournal of Immunology
Volume194
Issue number10
DOIs
StatePublished - Jan 1 2015

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Macrophages
Phenotype
Neoplasms
Tumor Microenvironment
Therapeutic Uses
interleukin-21
T-Lymphocytes
Therapeutics
Natural Killer Cells
Breast Neoplasms

ASJC Scopus subject areas

  • Immunology

Cite this

Intratumoral delivery of IL-21 overcomes anti-Her2/Neu resistance through shifting tumor-associated macrophages from M2 to M1 phenotype. / Xu, Meng; Liu, Mingyue; Du, Xuexiang; Li, Sirui; Li, Hang; Li, Xiaozhu; Li, Ying; Wang, Yang; Qin, Zhihai; Fu, Yang Xin; Wang, Shengdian.

In: Journal of Immunology, Vol. 194, No. 10, 01.01.2015, p. 4997-5006.

Research output: Contribution to journalArticle

Xu, Meng ; Liu, Mingyue ; Du, Xuexiang ; Li, Sirui ; Li, Hang ; Li, Xiaozhu ; Li, Ying ; Wang, Yang ; Qin, Zhihai ; Fu, Yang Xin ; Wang, Shengdian. / Intratumoral delivery of IL-21 overcomes anti-Her2/Neu resistance through shifting tumor-associated macrophages from M2 to M1 phenotype. In: Journal of Immunology. 2015 ; Vol. 194, No. 10. pp. 4997-5006.
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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.",
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AU - Li, Xiaozhu

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