Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida, USA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Immunother Cancer. 2022 Jun;10(6). doi: 10.1136/jitc-2022-004841.
Human epidermal growth factor receptor 2 (HER2) targeted antibodies in combination with chemotherapy has improved outcomes of HER2 positive (pos) breast cancer (BC) but toxicity of therapy remains a problem. High levels of tumor-infiltrating lymphocytes are associated with increased pathologic complete responses for patients treated with neoadjuvant therapy. Here we sought to investigate whether delivery of intratumoral (i.t.) multiepitope major histocompatibility complex (MHC) class II HER2 peptides-pulsed type I polarized dendritic cells (HER2-DC1) in combination with anti-HER2 antibodies without chemotherapy could enhance tumor regression by increasing anti-HER2 lymphocyte infiltration into the tumor.
BALB/c mice bearing orthotopic TUBO tumors, BALB/c mice bearing subcutaneous (s.c.) CT26 hHER2 tumors, or BALB-HER2/neu transgenic mice were all treated with i.t. or s.c. HER2-DC1, anti-HER2 antibodies, paclitaxel, T-DM1 or in combination. Immune response, host immune cells and effector function were analyzed using flow cytometry, interferon-γ ELISA and cytokine/chemokine arrays. The contributions of CD4 and CD8 T cells and antibody dependent cellular cytotoxicity (ADCC) were assessed using depleting antibodies and FcγR KO mice. Molecular changes were evaluated by immunohistochemistry and western blot.
HER2-DC1 combined with anti-HER2 antibodies delivered i.t. compared to s.c. induced complete tumor regression in 75-80% of treated mice, with increased tumor infiltrating CD4 and CD8 T, B, natural killer T cells (NKT) and natural killer cells, and strong anti-HER2 responses in all HER2 BC models tested. The therapy caused regression of untreated distant tumors. Labeled HER2-DC1 migrated prominently into the distant tumor and induced infiltration of various DC subsets into tumors. HER2-DC1 i.t. combined with anti-HER2 antibodies displayed superior antitumor response compared to standard chemotherapy with anti-HER2 antibodies. Lasting immunity was attained which prevented secondary tumor formation. The presence of CD4 and CD8 T cells and ADCC were required for complete tumor regression. In the HER2 BC models, HER2-DC1 i.t. combined with anti-HER2 antibodies effectively diminished activation of HER2-mediated oncogenic signaling pathways.
HER2-DC1 i.t. with anti-HER2 antibodies mediates tumor regression through combined activation of T and B cell compartments and provides evidence that HER2-DC1 i.t. in combination with anti-HER2 antibodies can be tested as an effective alternative therapeutic strategy to current chemotherapy and anti-HER2 antibodies in HER2 BC.
人表皮生长因子受体 2（HER2）靶向抗体联合化疗改善了 HER2 阳性（pos）乳腺癌（BC）的预后，但治疗毒性仍然是一个问题。高水平的肿瘤浸润淋巴细胞与接受新辅助治疗的患者的病理完全缓解率增加相关。在这里，我们试图研究是否通过向荷瘤（i.t.）多表位主要组织相容性复合物（MHC）II 类 HER2 肽脉冲 I 型极化树突状细胞（HER2-DC1）联合抗 HER2 抗体而不联合化疗，可以通过增加抗 HER2 淋巴细胞浸润肿瘤来增强肿瘤消退。
携带原位 TUBO 肿瘤的 BALB/c 小鼠、携带皮下（s.c.）CT26 hHER2 肿瘤的 BALB/c 小鼠或 BALB-HER2/neu 转基因小鼠均接受 i.t.或 s.c. HER2-DC1、抗 HER2 抗体、紫杉醇、T-DM1 或联合治疗。使用流式细胞术、干扰素-γ ELISA 和细胞因子/趋化因子阵列分析免疫反应、宿主免疫细胞和效应功能。使用耗竭抗体和 FcγR KO 小鼠评估 CD4 和 CD8 T 细胞和抗体依赖性细胞毒性（ADCC）的贡献。通过免疫组织化学和 Western blot 评估分子变化。
与 s.c.相比，i.t.给予 HER2-DC1 联合抗 HER2 抗体可使 75-80%的治疗小鼠完全消退肿瘤，所有测试的 HER2 BC 模型中均增加了肿瘤浸润的 CD4 和 CD8 T、B、自然杀伤 T 细胞（NKT）和自然杀伤细胞，并产生强烈的抗 HER2 反应。该疗法导致未治疗的远处肿瘤消退。标记的 HER2-DC1 明显迁移到远处肿瘤，并诱导各种 DC 亚群浸润肿瘤。与抗 HER2 抗体的标准化疗相比，i.t.联合抗 HER2 抗体的 HER2-DC1 显示出优越的抗肿瘤反应。获得了防止二次肿瘤形成的持久免疫力。CD4 和 CD8 T 细胞和 ADCC 的存在是完全肿瘤消退所必需的。在 HER2 BC 模型中，i.t.联合抗 HER2 抗体的 HER2-DC1 有效抑制了 HER2 介导的致癌信号通路的激活。
i.t.联合抗 HER2 抗体的 HER2-DC1 通过联合激活 T 和 B 细胞区室介导肿瘤消退，并提供了 HER2-DC1 i.t.联合抗 HER2 抗体可作为替代目前化疗和 HER2 BC 中抗 HER2 抗体的有效治疗策略的证据。
