期刊
MOLECULAR THERAPY
卷 29, 期 4, 页码 1541-1556出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2020.12.037
关键词
-
资金
- US Department of Defense [W81XWH-16-1-0385]
- Breast Cancer Research Foundation
- Pennies in Action
- Flow Cytometry, Analytic Microscopy Core Facility and Animal Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center [P30-CA076292]
The study reveals the impact of Th1 immune response on HER2 breast cancer, showing that IFN-gamma can regulate HER2 through the PDP pathway. Treatment with IFN-gamma or Th1-polarizing anti-HER2 vaccine can lead to decreased surface HER2 expression and induction of tumor senescence in HER2-resistant mammary carcinoma, demonstrating therapeutic potential through anti-tumor immunity.
HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and-resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-gamma caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-gamma or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-gamma synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-gamma that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据