Lee Sang Beom, Pan Jing, Xiong Donghai, Palen Katie, Johnson Bryon, Lubet Ronald A, Shoemaker Robert H, Green Jeffrey E, Fernando Romaine Ingrid, Sei Shizuko, You Ming, Wang Yian
Center for Cancer Prevention, Houston Methodist Cancer Center, Houston Methodist Research Institute, Weill Cornell College of Medicine, Houston, TX, USA.
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
NPJ Precis Oncol. 2023 Oct 25;7(1):108. doi: 10.1038/s41698-023-00461-1.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has a poor prognosis. TOP2A is a key enzyme in DNA replication and is a therapeutic target for breast and other cancers. TOP2A-specific Th1-promoting epitopes with optimal binding affinity to MHC II were identified using a combined scoring system. The multi-peptide TOP2A vaccine elicited a robust immunologic response in immunized mice, as demonstrated by the significant production of Th1 cytokines from immunized animals' splenocytes stimulated in vitro with TOP2A peptides. Anti-tumor efficacy of the TOP2A vaccine was demonstrated in a syngeneic TNBC mouse model, in which pre-graft preventive vaccination was associated with significantly decreased tumor growth as compared to adjuvant control. In a genetically engineered mouse (GEM) model of TNBC, vaccinated animals demonstrated a significant reduction in tumor incidence and average tumor volume compared to adjuvant control. Finally, we examined TCR sequences in CD4 tumor Infiltrating lymphocytes (TIL) from vaccinated mice and found that the TIL contained TCR sequences specific to the three vaccine peptides. These data indicate that our newly developed multi-peptide TOP2A vaccine is highly immunogenic, elicits TILs with vaccine specific TCRs, and is highly effective in preventing and intercepting TNBC development and progression in vivo.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，预后较差。TOP2A是DNA复制中的关键酶，是乳腺癌和其他癌症的治疗靶点。使用组合评分系统鉴定了与MHC II具有最佳结合亲和力的TOP2A特异性Th1促进表位。多肽TOP2A疫苗在免疫小鼠中引发了强烈的免疫反应，这通过用TOP2A肽体外刺激免疫动物的脾细胞后Th1细胞因子的大量产生得以证明。TOP2A疫苗的抗肿瘤功效在同基因TNBC小鼠模型中得到证实，其中与佐剂对照相比，移植前预防性疫苗接种与肿瘤生长显著降低相关。在TNBC的基因工程小鼠（GEM）模型中，与佐剂对照相比，接种疫苗的动物肿瘤发生率和平均肿瘤体积显著降低。最后，我们检查了接种疫苗小鼠的CD4肿瘤浸润淋巴细胞（TIL）中的TCR序列，发现TIL包含对三种疫苗肽特异的TCR序列。这些数据表明，我们新开发的多肽TOP2A疫苗具有高度免疫原性，能引发具有疫苗特异性TCR的TIL，并且在体内预防和拦截TNBC的发生和进展方面非常有效。
