Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy.
Cancer Immunol Res. 2018 Nov;6(11):1417-1425. doi: 10.1158/2326-6066.CIR-17-0572. Epub 2018 Aug 24.
Metastatic breast cancer is a fatal disease that responds poorly to treatment. Cancer vaccines targeting antigens expressed by metastatic breast cancer cells and cancer stem cells could function as anticancer therapies. Cripto-1 is an oncofetal protein overexpressed in invasive breast cancer and cancer-initiating cells. In this study, we explored the potential of a Cripto-1-encoding DNA vaccine to target breast cancer in preclinical mouse models. BALB/c mice and BALB-neuT mice were treated with a DNA vaccine encoding mouse Cripto-1 (mCr-1). BALB/c mice were challenged with murine breast cancer 4T1 cells or TUBO spheres; BALB-neuT mice spontaneously developed breast cancer. Tumor growth was followed in all mouse models and lung metastases were evaluated. assays were performed to identify the immune response elicited by vaccination. Vaccination against mCr-1 reduced primary tumor growth in the 4T1 metastatic breast cancer model and reduced lung metastatic burden. In BALB-neuT mice, because the primary tumors are Cripto-1 negative, vaccination against mCr-1 did not affect primary tumors but did reduce lung metastatic burden. Spheroid-cultured TUBO cells, derived from a BALB/neuT primary tumor, develop a cancer stem cell-like phenotype and express mCr-1. We observed reduced tumor growth in vaccinated mice after challenge with TUBO spheres. Our data indicate that vaccination against Cripto-1 results in a protective immune response against mCr-1 expressing and metastasizing cells. Targeting Cripto-1 by vaccination holds promise as an immunotherapy for treatment of metastatic breast cancer. .
转移性乳腺癌是一种治疗反应差的致命疾病。针对转移性乳腺癌细胞和癌症干细胞表达的抗原的癌症疫苗可以作为抗癌疗法。Cripto-1 是一种在浸润性乳腺癌和癌症起始细胞中过度表达的癌胚蛋白。在这项研究中，我们探索了编码 Cripto-1 的 DNA 疫苗靶向临床前小鼠模型中乳腺癌的潜力。BALB/c 小鼠和 BALB-neuT 小鼠用编码小鼠 Cripto-1（mCr-1）的 DNA 疫苗治疗。BALB/c 小鼠用鼠乳腺癌 4T1 细胞或 TUBO 球体进行挑战；BALB-neuT 小鼠自发发展为乳腺癌。在所有小鼠模型中监测肿瘤生长并评估肺转移。进行 分析以鉴定疫苗接种引起的免疫反应。针对 mCr-1 的疫苗接种减少了转移性乳腺癌 4T1 模型中的原发性肿瘤生长并减少了肺转移负担。在 BALB-neuT 小鼠中，由于原发性肿瘤为 Cripto-1 阴性，因此针对 mCr-1 的疫苗接种不会影响原发性肿瘤，但会减少肺转移负担。来自 BALB/neuT 原发性肿瘤的球体培养的 TUBO 细胞表现出类似于癌症干细胞的表型并表达 mCr-1。我们观察到用 TUBO 球体挑战后接种疫苗的小鼠肿瘤生长减少。我们的数据表明，针对 Cripto-1 的疫苗接种会导致针对表达 mCr-1 和转移细胞的保护性免疫反应。通过疫苗接种靶向 Cripto-1 有望成为治疗转移性乳腺癌的免疫疗法。
