Molecular Pathology Section, Laboratory of Immunogenetics, NIAID/NIH, Twinbrook 1, Room 1329, 5640 Fishers Lane, Rockville, MD, 20852, USA.
Cancer Immunol Immunother. 2018 Dec;67(12):1955-1965. doi: 10.1007/s00262-018-2251-8. Epub 2018 Nov 2.
Cancer vaccines have great potential in the fight against metastatic malignancies. Current anti-tumor immunotherapy is hindered by existing tolerance to tumor-associated antigens (TAA) and tumor escape using various mechanisms, highlighting the need for improved targets for immunotherapy. The cancer-testis antigen CTCFL/BORIS was discovered 16 years ago and possesses all features necessary for an ideal TAA. Recently CTCFL/BORIS has received additional attention as a target expressed in cancer stem cells (CSC). These cells drive tumor growth recurrence, metastasis, and treatment resistance. CTCFL/BORIS silencing leads to senescence and death of CSC. Therefore, an immunotherapeutic strategy that targets CTCFL/BORIS may lead to the selective destruction of CSC and potential eradication of metastatic disease. The high immunotherapeutic potential of CTCFL/BORIS antigen was shown in a stringent 4T1 mouse model of breast cancer. Using these highly metastatic, poorly immunogenic carcinoma cells inoculated into T-helper2 prone mice, we showed that DC fed with recombinant CTCFL/BORIS as an immunogen inhibited tumor growth and reduced the number of metastases in distant organs. About 20% of CTCFL/BORIS immunized animals were tumor free. 50% of animals remained metastasis free. Those having metastasis showed at least tenfold fewer metastases compared to controls. In a rat model of breast cancer, we showed that alphavirus-based CTCFL/BORIS immunotherapy was capable of cancer elimination as we were able to cure 50% of animals. Based on the above data, we believe that translation of CTCFL/BORIS-targeting immunotherapeutic strategies to the clinic will provide new avenues for improving survival of breast cancer patients with advanced metastatic disease.
癌症疫苗在对抗转移性恶性肿瘤方面具有巨大潜力。目前的抗肿瘤免疫疗法受到对肿瘤相关抗原（TAA）的现有耐受以及肿瘤通过各种机制逃避的限制，这突出表明需要改善免疫疗法的靶点。癌症睾丸抗原 CTCFL/BORIS 是 16 年前发现的，具有作为理想 TAA 所需的所有特征。最近，CTCFL/BORIS 作为在癌症干细胞（CSC）中表达的靶标受到了更多关注。这些细胞驱动肿瘤生长复发、转移和治疗耐药性。CTCFL/BORIS 沉默会导致 CSC 衰老和死亡。因此，针对 CTCFL/BORIS 的免疫治疗策略可能导致 CSC 的选择性破坏，并有可能根除转移性疾病。CTCFL/BORIS 抗原具有很高的免疫治疗潜力，在严格的 4T1 乳腺癌小鼠模型中得到了证明。使用这些高度转移性、免疫原性差的癌细胞接种到辅助性 T 细胞倾向的小鼠中，我们表明，用重组 CTCFL/BORIS 作为免疫原喂养的树突状细胞抑制肿瘤生长并减少远处器官转移的数量。大约 20%的 CTCFL/BORIS 免疫动物无肿瘤。50%的动物无转移。与对照组相比，有转移的动物的转移数量至少减少了十倍。在乳腺癌大鼠模型中，我们表明，基于甲病毒的 CTCFL/BORIS 免疫疗法能够消除癌症，因为我们能够治愈 50%的动物。基于上述数据，我们相信将 CTCFL/BORIS 靶向免疫治疗策略转化为临床将为改善晚期转移性乳腺癌患者的生存提供新途径。
