Clinical Science & Immunology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Breast Oncology, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
Clinical Science & Immunology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
Mol Ther. 2021 Apr 7;29(4):1541-1556. doi: 10.1016/j.ymthe.2020.12.037. Epub 2021 Jan 5.
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)-γ 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-γ 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-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.
HER2 阳性乳腺癌（BC）仍然是局部晚期或转移性 BC 患者的一个重大问题。我们研究了辅助性 T 细胞 1（Th1）免疫反应与蛋白酶体降解途径（PDP）在 HER2 敏感和耐药细胞中的关系。HER2 过表达部分是因为 E3 泛素连接酶 Cullin5（CUL5）降解 HER2，其经常发生突变或表达不足，而客户保护共伴侣细胞分裂周期蛋白 37（Cdc37）和热休克蛋白 90（Hsp90）增加，导致 HER2 生存能力下降。Th1 细胞因子干扰素（IFN）-γ导致 CUL5 表达增加，Cdc37 和 Hsp90 与 HER2 明显分离，导致 HER2 表面大量丢失，生长减少，并诱导肿瘤衰老。在 HER2 耐药的乳腺癌中，IFN-γ或 Th1 极化抗 HER2 疫苗与抗 HER2 抗体联合使用时，可增加肿瘤内 CUL5 表达，减少 HER2 表面表达，并诱导肿瘤衰老，具有显著的治疗活性。IFN-γ与多种 HER2 靶向药物协同作用，降低 HER2 表面表达，从而减少肿瘤生长。这些数据表明 IFN-γ 通过 PDP 途径调节 HER2 的新功能，并为通过抗肿瘤免疫影响 HER2 反应提供了机会。
