Osada Takuya, Morse Michael A, Hobeika Amy, Diniz Marcio A, Gwin William R, Hartman Zachary, Wei Junping, Guo Hongtao, Yang Xiao-Yi, Liu Cong-Xiao, Kaneko Kensuke, Broadwater Gloria, Lyerly H Kim
Department of Surgery, Duke University Medical Center, Durham, NC, USA.
Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Oncoimmunology. 2017 Apr 12;6(6):e1315495. doi: 10.1080/2162402X.2017.1315495. eCollection 2017.
Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies. Using novel human HER3 transgenic mouse models of breast cancer, we demonstrate that immunization with recombinant adenoviral vectors encoding full length human HER3 (Ad-HER3-FL) induces HER3-specific T cells and antibodies, alters the T cell infiltrate in tumors, and influences responses to immune checkpoint inhibitions. Both preventative and therapeutic Ad-HER3-FL immunization delayed tumor growth but were associated with both intratumoral PD-1 expressing CD8 T cells and regulatory CD4 T cell infiltrates. Immune checkpoint inhibition with either anti-PD-1 or anti-PD-L1 antibodies increased intratumoral CD8 T cell infiltration and eliminated tumor following preventive vaccination with Ad-HER3-FL vaccine. The combination of dual PD-1/PD-L1 and CTLA4 blockade slowed the growth of tumor in response to Ad-HER3-FL in the therapeutic model. We conclude that HER3-targeting vaccines activate HER3-specific T cells and induce anti-HER3 specific antibodies, which alters the intratumoral T cell infiltrate and responses to immune checkpoint inhibition.
人表皮生长因子家族成员3（HER3）是一种与表皮生长因子受体（EGFR）和人表皮生长因子受体2（HER2）形成关键异二聚体的伴侣蛋白，其表达会促进乳腺癌和其他上皮性恶性肿瘤的生物学行为更具侵袭性。因此，抑制HER3可能广泛适用于治疗由EGFR和HER2驱动的肿瘤。尽管缺乏功能性激酶结构域限制了受体酪氨酸激酶抑制剂的使用，但HER3含有T细胞和抗体的抗原靶点。利用新型人HER3转基因乳腺癌小鼠模型，我们证明用编码全长人HER3的重组腺病毒载体（Ad-HER3-FL）进行免疫可诱导HER3特异性T细胞和抗体，改变肿瘤中的T细胞浸润，并影响对免疫检查点抑制的反应。预防性和治疗性Ad-HER3-FL免疫均延迟了肿瘤生长，但与肿瘤内表达程序性死亡受体1（PD-1）的CD8 T细胞和调节性CD4 T细胞浸润均有关。用抗PD-1或抗程序性死亡受体配体1（PD-L1）抗体进行免疫检查点抑制可增加肿瘤内CD8 T细胞浸润，并在用Ad-HER3-FL疫苗进行预防性接种后消除肿瘤。在治疗模型中，双重阻断PD-1/PD-L1和细胞毒性T淋巴细胞相关蛋白4（CTLA4）可减缓Ad-HER3-FL治疗后肿瘤的生长。我们得出结论，靶向HER3的疫苗可激活HER3特异性T细胞并诱导抗HER3特异性抗体，从而改变肿瘤内T细胞浸润和对免疫检查点抑制的反应。
