Nocera Nadia F, Lee M Catherine, De La Cruz Lucy M, Rosemblit Cinthia, Czerniecki Brian J
Department of Surgery, University of Pennsylvania Perelman School of Medicine Philadelphia, PA, USA.
Comprehensive Breast Program, H. Lee Moffitt Cancer Center Tampa, FL, USA.
Front Pharmacol. 2016 Oct 6;7:356. doi: 10.3389/fphar.2016.00356. eCollection 2016.
The ErbB/B2 (HER-2/neu) oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy. Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast. Th1 cell production of the cytokines interferon gamma (IFNγ) and TNFα can enhance MHC class I expression, PD-L1 expression, augment apoptosis and tumor senescence, and enhances growth inhibition of many anti-breast cancer agents, including anti-estrogens and HER-2 targeted therapies. Recently, we have identified that a loss of anti-HER-2 CD4 Th1 in peripheral blood occurs during breast tumorigenesis and is dramatically diminished, even in Stage I breast cancers. The loss of anti-HER-2 Th1 response is specific and not readily reversed by standard therapies. In fact, this loss of anti-HER-2 Th1 response in peripheral blood correlates with lack of complete response to neoadjuvant therapy and diminished disease-free survival. This defect can be restored with HER-2 vaccinations in both DCIS and IBC. Correcting the anti-HER-2 Th1 response may have significant impact in improving response to HER-2 targeted therapies. Development of immune monitoring systems for anti-HER-2 Th1 to identify patients at risk for recurrence could be critical to improving outcomes, since the anti-HER-2 Th1 response can be restored by vaccination. Correction of the cellular immune response against HER-2 may prevent recurrence in high-risk patients with DCIS and IBC at risk of developing new or recurrent breast cancer.
ErbB/B2（HER-2/neu）癌基因家族在包括乳腺癌、卵巢癌和胃癌在内的多种肿瘤类型的发生发展及转移扩散中起关键作用。在乳腺癌中，HER-2/neu在大部分导管原位癌（DCIS）病变的早期疾病发展过程中表达，其表达与侵袭和复发风险增加相关。用曲妥珠单抗或帕妥珠单抗等抗体靶向HER-2可提高生存率，但疾病范围更广的患者可能会对治疗产生耐药性。有趣的是，对HER-2靶向治疗的反应与乳腺中免疫反应基因的存在相关。Th1细胞产生的细胞因子干扰素γ（IFNγ）和肿瘤坏死因子α（TNFα）可增强MHC I类表达、PD-L1表达，增强细胞凋亡和肿瘤衰老，并增强包括抗雌激素和HER-2靶向治疗在内的许多抗乳腺癌药物的生长抑制作用。最近，我们发现，在乳腺肿瘤发生过程中，外周血中抗HER-2 CD4 Th1细胞会减少，即使在I期乳腺癌中也是如此，且显著减少。抗HER-2 Th1反应的丧失是特异性的，标准治疗不易逆转。事实上，外周血中抗HER-2 Th1反应的丧失与对新辅助治疗缺乏完全反应及无病生存期缩短相关。在DCIS和炎性乳腺癌（IBC）中，通过HER-2疫苗接种可恢复这种缺陷。纠正抗HER-2 Th1反应可能对改善HER-2靶向治疗的反应有重大影响。开发针对抗HER-2 Th1的免疫监测系统以识别有复发风险的患者对于改善治疗结果可能至关重要，因为抗HER-2 Th1反应可通过疫苗接种恢复。纠正针对HER-2的细胞免疫反应可能预防有发生新发或复发性乳腺癌风险的DCIS和IBC高危患者复发。
